EP0200777A1 - New amino compounds, preparation process thereof, utilization thereof and drugs containing them - Google Patents

New amino compounds, preparation process thereof, utilization thereof and drugs containing them

Info

Publication number
EP0200777A1
EP0200777A1 EP85905795A EP85905795A EP0200777A1 EP 0200777 A1 EP0200777 A1 EP 0200777A1 EP 85905795 A EP85905795 A EP 85905795A EP 85905795 A EP85905795 A EP 85905795A EP 0200777 A1 EP0200777 A1 EP 0200777A1
Authority
EP
European Patent Office
Prior art keywords
hydrogen
compounds
formula
alkyl
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP85905795A
Other languages
German (de)
French (fr)
Inventor
Jörg Senn-Bilfinger
Volker Figala
Bernhard Kohl
Hartmann Schaefer
Richard Riedel
Georg Rainer
Kurt Klemm
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Byk Gulden Lomberg Chemische Fabrik GmbH filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Publication of EP0200777A1 publication Critical patent/EP0200777A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/28—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/12—1,4-Dioxanes; Hydrogenated 1,4-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • New amino compounds Process for their preparation, their application and medicinal products containing them
  • the invention relates to new amino compounds, processes for their preparation, their use and medicaments containing them.
  • the compounds according to the invention are used in the pharmaceutical industry as intermediates and for the manufacture of medicaments.
  • Pyridylsulfinylbenzimidazole described that are said to have gastric acid secretion-inhibiting properties.
  • the European patent application 0 074 3.1 describes the use of a number of benzimidazole derivatives for inhibiting gastric acid secretion.
  • the German Offenlegungsschrift 34 04 610 describes further benzimidazole derivatives as cell-protecting agents for the gastrointestinal tract and as inhibitors for gastric acid secretion in mammals.
  • the invention relates to new amino compounds of the formula I.
  • R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and wherein R1, R2, R3 and R4 can be at any position
  • R1 is hydrogen or C 1 -C 6 alkyl
  • R2 is hydrogen, cyano, nitro, halogen, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkyl, C 1 -C 2 alkylendloxy -C 1 -C 4 alkyl, hydroxy-C 1 -C 4 alkyl, cyano-C 1 -C 4 alkoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkoxy, C 1 -C 6 alkylcarbonyl , C 1 -C 4 alkoxycarbonyl, phenyl, phenoxy, phenoxy-C 1 -C 4 alkyl, phenoxy-C 1 -C 4 alkoxy, phen-C 1 -C 4 alkyl, phen-C 1 -C 4 - alkoxy or benzoyl means R3 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6
  • R5 denotes hydrogen or a group which can easily be split off under physiological conditions
  • R6 represents hydrogen or C 1 -C 4 alkyl
  • R7 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or together with R8a is C 2 -C 3 -alkylene,
  • R8a is hydrogen, C 1 -C 4 -alkyl, C 3 -C 4 -alkenyl, together with R7 C 2 -C 3 alkylene, together with R9 C 2 -C 3 -alkylene or together with R8b optionally C 4 - interrupted by oxygen C 6 alkylene means
  • R8b is hydrogen, C 1 -C 4 -alkyl, C 3 -C 4 -alkenyl, C 1 -C 4 -alkylcarbonyl or together with RBa C 4 -C 6 -alkylene optionally interrupted by oxygen,
  • R9 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or together with R8a is C 2 -C 3 -alkylene,
  • R10 represents hydrogen or C 1 -C 4 alkyl and n represents the numbers 0 or 1, and the salts of these compounds.
  • Halogen in the sense of the present invention is bromine, chlorine and fluorine.
  • C 1 -C 6 alkyl represents straight-chain, branched or cyclic alkyl radicals.
  • Straight-chain alkyl radicals are the hexyl, pentyl, butyl, propyl, ethyl, and especially the methyl radical.
  • Branched alkyl radicals are, for example, the neopentyl, 1-butyl, sec-butyl, t-butyl and the isopropyl radical.
  • the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals may be mentioned as cyclic alkyl radicals.
  • C 1 -C 6 alkoxy represents straight-chain or branched alkoxy radicals. Examples include the hexyloxy, neopentyloxy, butoxy, 1-butoxy, sec-butoxy, t-butoxy, propoxy, isopropoxy, ethoxy and especially the methoxy radical.
  • C 1 -C 4 alkoxy represents straight-chain or branched alkoxy radicals; Examples include the butoxy, i-butoxy, sec. butoxy, t-butoxy, propoxy, isopropoxy, ethoxy and in particular the methoxy radical.
  • C 1 -C 4 alkyl represents straight-chain or branched alkyl radicals;
  • the butyl, i-butyl, sec-butyl, t-butyl, propyl, isopropyl, ethyl and especially the methyl radical may be mentioned.
  • C 1 -C 4 alkoxy-C 1 -C 4 alkyl represents C 1 -C 4 alkyl which is substituted by C 1 -C 4 alkoxy. Examples include the ethoxymethyl, propoxybutyl, methoxymethyl and in particular the methoxyethyl radical.
  • C 1 -C 2 -alkylenedioxy-C 1 -C 4 -alkyl represents C 1 -C 4 -alkyl which is substituted by an alkylenedioxy radical.
  • the ethylenedioxymethyl radical may be mentioned.
  • Hydroxy-C 1 -C 4 alkyl represents C 1 -C 4 alkyl which is substituted by a hydroxy radical.
  • a hydroxy radical For example, the 3-hydroxybutyl, 2-hydroxyisopropyl, 2-hydroxyethyl and especially the hydroxymethyl radical may be mentioned.
  • Cyan-C 1 -C 4 alkoxy stands for C 1 -C 4 alkoxy which is substituted by a cyan radical.
  • the cyanomethoxy radical may be mentioned.
  • C 1 -C 4 alkoxy-C 1 -C 4 alkoxy represents C 1 -C 4 alkoxy, which is replaced by C 1 -C 4 - Alkoxy is substituted.
  • Examples include the ethoxyethoxy, methoxypropoxy, ethoxymethoxy and in particular the methoxyethoxy radical.
  • C 1 -C 6 alkylcarbonyl represents C 1 -C 6 alkyl bonded to a carbonyl group.
  • the propionyl, butyryl, i-butyryl and in particular the cyclopropylcarbonyl and acetyl radicals may be mentioned.
  • C 1 -C 4 alkoxycarbonyl represents a carbonyl group bonded to C 1 -C 4 - alkoxy. Examples include the ethoxycarbonyl and methoxycarbonyl radicals.
  • Phenoxy-C 1 -C 4 alkyl stands for C 1 -C 4 alkyl which is substituted by a phenoxy radical.
  • the phenoxypropyl and the phenoxyethyl radical may be mentioned.
  • Phenoxy-C 1 -C 4 alkoxy stands for C 1 -C 4 alkoxy which is substituted by a phenoxy radical.
  • the phenoxyethoxy and the phenoxypropoxy radical may be mentioned.
  • Phen-C 1 -C 4 alkyl represents C 1 -C 4 alkyl which is substituted by a phenyl radical. Examples include the phenethyl and especially the benzyl radical.
  • Phen-C 1 -C 4 alkoxy stands for C 1 -C 4 alkoxy which is substituted by a phenyl radical. Examples include the 2-phenyl-ethoxy and the benzyloxy radical.
  • Examples of 1, 1, 2-trifluoroethoxy, perfluoropropoxy, perfluoroethoxy and, in particular, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, and the like as completely or predominantly substituted by fluorine are C 1 -C 4 alkoxy. , the 2,2,2-trifluoroethoxy and the Oifluormethoxyrest called.
  • Examples of the completely or partially substituted by fluorine-substituted C 1 -C 2 -alkylenedioxy are 1,1-difluoroethylenedioxy- (-O-CF 2 -CH 2 -O-), 1,1,2,2-tetrafluoroethylenedioxy- (- O-CF 2 -CF 2 -O-) and in particular the difluoromethylene dioxy- (-O-CF 2 -O-) and the 1,1,2-trifluoroethyleneendloxy- rest (-O-CF 2 -CHF-O-).
  • a group R5 which can easily be split off under physiological conditions, is a substituent which is separated from the nitrogen atom by, if appropriate, enzymatically catalyzed hydrolysis to form an NH bond, whereby it itself - with the attachment of a hydroxyl group - is converted into a physiologically acceptable and in particular pharmacologically compatible compound .
  • All types of substituted carbonyl groups such as the alkylcarbonyl, arylcarbonyl, aralkylcarbonyl,
  • Alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl or the optionally substituted carbamoyl group examples include the methoxycarbonyl, t-butoxycarbonyl, benzoyl, phenylcarbamoyl and dimethylcarbamoyl groups.
  • C 2 -C 3 alkylene which is formed jointly by R8a and R7 or R8a and R9, stands for ethylene or propylene.
  • C 3 -C 4 alkenyl represents the but-2-enyl, the but-3-enyl and in particular the allyl radical.
  • C 4 -C 6 alkylene which may be interrupted by oxygen represents - (CH 2 ) 4 -, - (CH 2 ) 5 -, - (CH 2 ) 6 - or - (CH 2 ) 2 -O- (Ch 2 ) 2 -, so that for the radicals R8a and R8b together with the nitrogen atom to which they are attached there is a pyrrolidlno, piperidino, perhydroazepino or morpholino radical.
  • C 1 -C 4 alkylcarbonyl represents C 1 -C 4 alkyl bonded to a carbonyl group.
  • the proponyl, butyryl and especially the acetyl radical may be mentioned.
  • Suitable salts for compounds of the formula I in which n is the number 0 are preferably all acid addition salts. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids commonly used in galenics. Pharmacologically incompatible salts, which can initially be obtained as process products, for example in the preparation of the compounds according to the invention, are characterized by Methods known to the person skilled in the art converted into pharmacologically acceptable salts.
  • Suitable as such are, for example, water-soluble and water-insoluble slurry addition salts, such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, cltrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosallcylate, maleate, laurate, malate, fumarate Succinate, oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate.
  • water-soluble and water-insoluble slurry addition salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, cltrate, gluconate, benzoate, hibenzate, fend
  • the preferred salts are basic salts, in particular pharmacologically compatible salts with inorganic and organic bases commonly used in galenics.
  • Lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium or guanidinium salts may be mentioned as examples of basic salts.
  • R3 and R4 together mean completely or partially substituted by fluorine-substituted C 1 -C 2 -alkylenedioxy or chlorotrifluoroethylenedloxy, the substituents R3 and R4 are bonded in neighboring positions on the benzo part of the benzimidazole ring.
  • One embodiment (embodiment a) of the invention are compounds of the formula I in which R7 and R9 are hydrogen and R1, R2, R3, R4, R5, R6, R8a, R8b, R10 and n have the meanings given above, and their salts.
  • a further embodiment (embodiment b) of the invention are compounds of the formula I in which R7 is C 1 -C 4 -alkyl, R9 is hydrogen and R1, R2, R3, R4, R5, R6, R8a, R8b, R10 and n the have meanings given above, and their salts.
  • R1 is hydrogen or C 1 -C 4 alkyl
  • R2 is hydrogen, halogen, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkyl, hydroxy-C 1 -C 4 alkyl, C 1 -C 4 alkoxy-C 1 -C 4 alkoxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, phenyl, Phenoxy, phenoxy-C 1 -C 4 -alkyl, phenoxy-C 1 -C 4 -alkoxy, phen-C 1 -C 4 -alkyl, phen-C 1 -C 4 -alkoxy or benzoyl,
  • R3 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, completely or predominantly substituted by fluorine-substituted C 1 -C 4 -alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R4 C 1 -C 2 -alkylenedioxy or chlorotrifluoroethylenedloxy which is wholly or partly substituted by fluorine,
  • R4 is completely or predominantly substituted by fluorine-substituted C 1 -C 4 -alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R3 completely or partially substituted by fluorine-substituted C 1 -C 2 -alkylene dioxy or chlorotrifluoroethylene doxy ,
  • R5 means hydrogen
  • R6 represents hydrogen or C 1 -C 4 alkyl
  • R8 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or together with R8a is C 2 -C 3 -alkylene,
  • R8a is hydrogen, C 1 -C 4 alkyl, together with R7 is C 2 -C 3 alkylene, together with R9 is C 2 -C 3 alkylene or together with R8b is C 4 -C 6 alkylene which is optionally interrupted by oxygen,
  • R8b is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylcarbonyl or, together with R8a, C 4 -C 6 alkylene which is optionally interrupted by oxygen,
  • R9 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or together with R8a is C 2 -C 3 -alkylene,
  • R10 represents hydrogen or C 1 -C 4 alkyl and n represents the numbers 0 or 1, and the salts of these compounds.
  • An embodiment (embodiment a ') of the compounds to be emphasized are those of the formula I in which R7 and R9 are hydrogen and R1, R2, R3, R4, R5, R6, R8a, R8b, R10 and n have the meanings given for the compounds to be emphasized , and their salts.
  • a further embodiment (embodiment b ') of the compounds to be emphasized are those of the formula I in which R7 is C 1 -C 4 -alkyl, R9 is hydrogen and R1, R2, R3, R4, R5, R6, R8a, R8b, R10 and n have the meanings given for the compounds to be emphasized, and their salts.
  • Preferred compounds according to the invention are those in which
  • R1 is hydrogen, methyl or ethyl
  • R2 is hydrogen, chlorine, fluorine, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, acetyl, methoxycarbonyl or ethoxycarbonyl
  • R3 is hydrogen, methyl, ethyl, methoxy, ethoxy, 1,1,2,2 -Tetrafluoro-ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy or together with R4 means difluoromethyleneendloxy, 1,1,2-trifluoroethylene dioxy or 1-chloro-1,2,2-trifluoroethylene dioxy,
  • R4 denotes 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trlfluoroethoxy, difluoromethoxy or together with R3 difluoromethylene-dioxy, 1,1,2-trifluoroethylene-dioxy or 1-chloro-1,2,2-trifluoroethylene-dioxy, R5 Hydrogen means
  • RB means hydrogen, methyl or ethyl
  • R7 is hydrogen, methyl, ethyl, methoxy, ethoxy or together with R8a
  • Ethylene or propylene means R8a is hydrogen, methyl, ethyl, together with R7 ethylene or propylene, together with R9 ethylene or propylene or together with R8b and the nitrogen atom, to which both are bound, pyrrolidino, piperidino or morpholino means R8b hydrogen, Methyl, ethyl, acetyl or together with R8a and the nitrogen atom, to which both are bound, means pyrrolidino, piperidino or morpholino,
  • R9 is hydrogen, methyl, ethyl, methoxy, ethoxy or together with R8a
  • Ethylene or propylene means R10 means hydrogen, methyl or ethyl and n represents the numbers 0 or 1, and the salts of these compounds.
  • An embodiment (embodiment a ′′) of the preferred compounds are those of the formula I in which R7 and R9 are hydrogen and Rl, R2, R3, R4, R5, R6, R8a, R8b, R10 and n are the meanings given for the preferred compounds and their salts.
  • a further embodiment (embodiment b '') of the preferred compounds are those of the formula I in which R7 is methyl or ethyl, R9 is hydrogen and R1, 12, R3, R4, R5, R6, R8a, R8b, R10 and n have the meanings given for the preferred compounds, and their salts.
  • Particularly preferred compounds according to the invention are those in which R1 is hydrogen,
  • R2 means hydrogen
  • R3 is hydrogen or together with R4 difluoromethyleneendloxy
  • R4 denotes 1,1,2,2-tetrafluoroethoxy, Dlfluormethoxy or together with R3 Difluormethylenendloxy, R5 means hydrogen,
  • R6 means hydrogen
  • R7 means hydrogen or methyl
  • R8a is methyl or together with R8b and the nitrogen atom, to which both are bound, means pyrrolidino or morpholino
  • R8b is methyl or together with R8a and the nitrogen atom, to which both are bonded, means pyrrolidino or morpholino
  • R9 means hydrogen
  • R10 represents hydrogen and n represents the numbers 0 or 1, and the salts of these compounds.
  • the substituents R3 and R4 are in particular in the 5- and 6-position of the benzimidazole.
  • the invention further relates to a process for the preparation of the compounds of the formula I in which R1, R2, R3, R4, R5, R6, R7, R8a, R8b, R9, R10 and n have the meanings given above, and their salts.
  • Y, Y ", Z, Z 'and Z" represent suitable leaving groups
  • Y' represents a leaving or reactive group
  • M stands for an alkali metal atom (Li, Na or K)
  • M ' stands for the equivalent of a metal atom
  • R1, R2, R3, R4, RS, RB, R7, R8a, R8b, R9, R10 and n have the meanings given above.
  • the compounds II-XIV may be used in such or, if appropriate, in the form of their salts.
  • compounds I are prepared from starting compounds II to XII in which R1, R2, R3, R4, R5, R6, R7, R8a, R8b, R9, R10 and n are defined as specified above.
  • a suitable leaving group Y is, for example, a group which, together with the sulfinyl group to which it is attached, forms a reactive sulfinic acid derivative.
  • suitable leaving groups Y are alkoxy, dialkylamino or alkyl mercapto groups.
  • a suitable outlet or Reactive group Y ' is a group which is able to react with a secondary amino group with elimination of HY' or with addition.
  • R5 ' is for example a leaving group which together with the carbonyl group to which it is attached is a reactive carboxylic acid derivative, e.g. an acid halide.
  • the general formula R5'-Y '(XIII) also encompasses those compounds (precursors of the group R5 which can easily be split off under physiological conditions) in which Y' represents a reactive group (for example isonitriles) which are involved in the reaction with the secondary amino group no condensation with elimination of HY 'but an addition to form the desired cleavable group R5.
  • the leaving group Y ′′ is one of ordinary skill in the art for alkylation reactions common group that goes off during the alkylation - for example with dialkyl sulfate, alkyl fluorosulfonate or alkyl iodide.
  • the X equivalent of a metal atom M ' is, for example, an alkali metal (Li, Na or K), or an alkaline earth metal atom (eg Mg), which is substituted by a halogen atom (eg Br, Grignard reagent), or any other optionally substituted metal atom which is known to react in the substitution reactions of organometallic compounds such as the metals mentioned above.
  • a metal atom M ' is, for example, an alkali metal (Li, Na or K), or an alkaline earth metal atom (eg Mg), which is substituted by a halogen atom (eg Br, Grignard reagent), or any other optionally substituted metal atom which is known to react in the substitution reactions of organometallic compounds such as the metals mentioned above.
  • the reaction of II with III is carried out in a manner known per se in suitable, preferably polar protic or aprotic solvents (such as methanol, isopropanol, dimethyl sulfoxide, acetone, dimethylformamide or acetonitrile) with or without water. It is carried out, for example, in the presence of a proton acceptor.
  • suitable, preferably polar protic or aprotic solvents such as methanol, isopropanol, dimethyl sulfoxide, acetone, dimethylformamide or acetonitrile
  • a proton acceptor Alkali metal hydroxides such as sodium hydroxide, alkali metal carbonates such as potassium carbonate or tertiary amines such as pyridine, trlethylamine or ethyldiisopropylamine are suitable as such.
  • reaction can also be carried out without a proton acceptor, with the acid addition salts optionally being able to be separated off in a particularly pure form, depending on the nature of the starting compounds.
  • the reaction temperature can be between 0 ° and 150 ° C, in the presence of proton acceptors temperatures between 20 ° and 80 ° C and without proton acceptors between 60 ° and 120 ° C - especially the boiling point of the solvents used - are preferred.
  • the response times are between 0.5 and 12 hours.
  • reaction of VI with VII is preferred in polar, optionally water-containing solvents in the presence of a strong acid, for example hydrochloric acid, in particular at the boiling point of the used Solvent carried out.
  • a strong acid for example hydrochloric acid, in particular at the boiling point of the used Solvent carried out.
  • Suitable oxidizing agents are all reagents commonly used for the oxidation of sulfides to sulfoxides, in particular peroxy acids, e.g. Peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoic acid, peroxymaleic acid or preferably m-chloroperoxybenzoic acid.
  • the reaction time is (depending on the reactivity of the oxidizing agent and degree of dilution between -70 ° C and the boiling point of the solvent used, but preferably between -30 ° C and + 20 ° C.
  • Oxidation with halogens or with hypohalites has also been found to be advantageous (eg with aqueous sodium hypochlorite solution), which is expediently carried out at temperatures between 0 ° and 30 ° C.
  • reaction is advantageously carried out in inert solvents, for example aromatic or chlorinated hydrocarbons, such as benzene, toluene, dichloromethane or chloroform, preferably in esters or ethers, such as ethyl acetate, isopropyl acetate or dloxane.
  • aromatic or chlorinated hydrocarbons such as benzene, toluene, dichloromethane or chloroform
  • esters or ethers such as ethyl acetate, isopropyl acetate or dloxane.
  • the reaction of IX with X is preferably carried out in inert solvents, as are usually used for the reaction of enolate ions with alkylating agents.
  • inert solvents such as 8enzene or toluene may be mentioned.
  • the reaction temperature is (depending on the nature of the alkali metal atom M and the leaving group Z) generally between 0 ° and 120 ° C, with the boiling point of the solvent used being preferred.
  • M represents Li (lithium) and Z Cl (chlorine) and the reaction is carried out in benzene]
  • the boiling point of benzene 80 ° C.
  • the compounds XI are reacted with the compounds XI I in a manner known per se, as is known to the person skilled in the art for the reaction organorga African connections is common.
  • reaction according to process variant f) is carried out in a manner known to those skilled in the art in suitable solvents such as tetrahydrofuran or acetone tril, optionally with the addition of a base (if Y 'represents a leaving group) or without addition of base (if Y' represents a reactive group).
  • suitable solvents such as tetrahydrofuran or acetone tril
  • this reaction gives mixtures of isomers which have to be separated by suitable separation processes (e.g. chromatography).
  • Solvolysis according to process variant g) is carried out in a manner known to those skilled in the art in suitable water-containing or water-splitting alkaline or acidic solutions, at room temperature or, if desired, with heating to the boiling point of the solvent used.
  • the compounds according to the invention are initially obtained either as such or in the form of their salts.
  • the salts are obtained by dissolving the free compounds in a suitable solvent, e.g. in a chlorinated hydrocarbon such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol (ethanol, isopropanol), an ether
  • the salts are obtained by filtration, reprecipitation, precipitation or by evaporation of the solvent. Salts obtained can be converted into the free compounds by alkalization or acidification, for example with aqueous sodium hydrogen carbonate or with dilute hydrochloric acid, which in turn can be converted into the salts. In this way, the compounds can be purified or pharmacologically unacceptable salts can be converted into pharmacologically acceptable salts.
  • the sulfoxides according to the invention are optically active compounds. Depending on the nature of the substituents R1 to R10, there may be additional chiral centers in the molecule (e.g. if R6 is not hydrogen).
  • the invention therefore encompasses both the enantiomers and diastereomers as well as their mixtures and racemates.
  • the enantiomers can be separated in a manner known per se (for example by preparing and separating corresponding diastereoisomeric compounds). However, the enantiomers can also be prepared by asymmetric synthesis, for example by reaction of optically active pure compounds XI or diastereoisomerically pure compounds XI with compounds XII [see K.K. Andersen, Tetrahedron Lett., 93 (1962)].
  • the compounds according to the invention are preferably synthesized by reacting II with III and, if appropriate, subsequent oxidation of the sulfide VIII formed.
  • the compounds II, IV, VI, IX, XI, XIII and XIV are either known, or they can be obtained analogously according to known regulations, starting from known or obtainable precursors [see e.g. DE-OS 28 48 531; J. Org. Chem. 44, 2907-2910 (1979); J. Org. Chem. 29, 1-11 (1964); DE-OS 20 29 556; J. Fluorine Chem. 18: 281-91 (1981); Synthesis 1980, 727-8].
  • the compounds III are new and also a subject of the invention. They are made from corresponding pyridines unsubstituted in the 4-position by N-oxidation (e.g. with hydrogen peroxide), nitration in the 4-position (e.g. with fuming nitric acid), exchange of the nitro group for a chlorine atom (e.g. with concentrated hydrochloric acid), reaction with an amine HN (R8a) R8b and corresponding further reactions, as described in EP-A-0 103 553 or EP-A-0 080 602, can be obtained in a manner known to those skilled in the art.
  • the compounds V, VII and XII are e.g. B. from the compounds III in catfish known to those skilled in the art.
  • Compounds X are prepared based on Z. Talik, Roczniki Chem. 35, 475 (1961).
  • Example 1 5.6 g (15 mmol) of 6- [4-dimethylamino-3-methylpyridyl- (2) -methylthiol-2,2-difluoro-5H- [1.3] -dioxolo- [4, 5-f] benzimidazole after chromatographic purification on silica gel (eluent ethyl acetate / ethanol / concentrated ammonia 20: 4: 1) and stirring with dichloromethane / diethyl ether 1.2 g (20% of theory) of the title compound of mp 170-171 ° C (decomposition).
  • Example 1 3.1 g (7.63 mmol) of 5-difluoromethoxy-2- [3-methyl-4-morpholinopyridyl- (2) -methylthio] -1H-benzimidazole are obtained after stirring with dichloromethane to 1 g ( 30% of theory) of the title compound of mp. 149-150 ° C (decomposition).
  • Example 1 1-g (2.5 mmol) of 2,2-difluoro-6- [3-methyl-4-pyrrolidinyl- (1) -pyridyl- (2) -methylthio] -5H- [1,3 ] -dioxolo- [4,5-f] benzimidazole after chromatography on silica gel (eluent: ethyl acetate / ethanol / concentrated ammonia 20: 4: 1) and stirring with water and subsequently ethanol 0.45 g (43% of theory) Title compound of mp 18G-181 ° C (decomposition).
  • Example A1 6.8 g (97% of theory) of 2-chloromethyl-4-methylaminopyridine hydrochloride, mp. 171-173 ° C., are obtained from 5 g (36.2 mmol) of 2-hydroxymethyl-4-methylaminopyridine .
  • Example A1 7.4 g (99% of theory) of colorless 2-chloromethyl-4-dimethylamino-6- is obtained from 5.6 g (33.7 mmol) of 4-dimethylamino-2-hydroxymethyl-6-methylpyridine. methylpyridine hydrochloride, mp. 162-168 ° C.
  • Example A1 4 g (approx. 95% of theory) of the very hygroscopic 4-acetylamino-2-chloromethylpyridine hydrochloride is obtained from 3.17 g (19.1 mmol) of 4-acetylamino-2-hydroxymethylpyridine. 140 ° C.
  • Example A1 3 g (18 mmol) of 4-dimethylamino-2-hydroxymethyl-3-methylpyridine gave 1.9 g (48% of theory) of 2-chloromethyl-4-dimethylamino-3-methylpyridine hydrochloride, mp 197 -199 ° C.
  • Example A1 23.7 g (94% of theory) of 2-chloromethyl-3-methyl-4-morpholinopyridine hydrochloride are obtained from 20 g (96 mmol) of 2-hydroxymethyl-3-methyl-4-morpholinopyridine from mp. 77-80 ° C.
  • Example A1 11 g (57 mmol) of 2-hydroxymethyl-3-methyl-4-pyrrolidinyl- (1) -pyridine gave 3.5 g (25% of theory) of 2-chloromethyl-3-methyl-4 -pyrrolidinyl- (1) -pyridine hydrochloride of mp. 88-90 ° C. The substance is hygroscopic.
  • the substance is isolated by extraction with methylene chloride, washing, drying and evaporation on a rotary evaporator.
  • a solution of 60 g (0.38 mol) of 4-chloro-2,3-dimethylpyridine-N-oxide in 120 ml of methanol and 120 ml of water is mixed with 100 mg of copper (dchloride and 80 ml of olmethylamine) in a laboratory autoclave with a Teflon lining. After sealing, the mixture is stirred for 55 h at 90 ° C.
  • Example B1 Analogously to Example B1, the title compound of mp 305 is obtained in 75% yield by reacting 4-trifluoromethoxy-1,2-phenylenediamine dihydrochloride (cf. CA. 55, 23408d, 1961) with potassium O-ethyldithiocarbonate and sodium hydroxide solution in ethanol -307 ° C (decomposed from toluene).
  • a sample is separated on a silica gel column with cyclohexane / ethyl acetate (4: 1) into two pure isomers with melting points 110, 5-111, 5 ° C and 120-121 ° C, whose NMR spectra on a 60 MHz Device in deuterochloroform are practically identical.
  • the compounds of the formula I according to the invention and their salts have valuable pharmacological properties which make them commercially usable. They clearly inhibit the magnesic acid secretion of warm-blooded animals and also have an excellent gastric and intestinal protective effect in warm-blooded animals. This gastric and intestinal protective effect is sometimes already observed when doses are administered which are below the acid secretion-inhibiting doses.
  • the compounds according to the invention are distinguished by the absence of significant side effects and a large therapeutic breadth.
  • Another aspect essential to the invention is that the compounds of the formula I have high chemical stability and a significant maximum activity in the pH range desired in each case.
  • stomach and intestinal protection means the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach), which are caused, for example, by microorganisms, bacterial toxins, Medications (e.g. certain anti-inflammatory drugs and anti-rheumatic drugs), chemicals (e.g. ethanol), stomach acid or stressful situations can be caused.
  • gastrointestinal inflammatory diseases and lesions such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach
  • Medications e.g. certain anti-inflammatory drugs and anti-rheumatic drugs
  • chemicals e.g. ethanol
  • the compounds according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art. Because of these properties, the compounds according to the invention and their pharmacologically tolerated salts are outstandingly suitable for use in human and veterinary medicine, and are used in particular for the treatment and prophylaxis of diseases of the stomach and intestines and of diseases which are based on excessive gastric acid secretion .
  • the high storage stability of the compounds according to the invention enables their problem-free use in pharmaceutical preparations.
  • the invention also relates to the invention bindings for use in the treatment and prophylaxis of the aforementioned diseases.
  • the invention also includes the use of the blindings according to the invention in the manufacture of medicaments which are used for the treatment and prophylaxis of the abovementioned diseases.
  • the invention further relates to medicaments which contain one or more compounds of the formula I according to the invention and / or their pharmacologically tolerable salts.
  • the pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art.
  • auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • solvents for example antioxidants, dispersants, emulsifiers, defoamers, taste correctives, preservatives, solubilizers, colorants or in particular permeation promoters and complexing agents (e.g. cyclodextrins) can be used.
  • the active ingredients can be administered orally, parenterally or percutaneously.
  • the active ingredient (s) when administered orally in a daily dose of about 0.05 to about 50, preferably 0.25 to 20, in particular 0.5 to 10 mg / kg body weight in the form of several, preferably 1 to 4 individual doses to achieve the desired result.
  • a daily dose of about 0.05 to about 50, preferably 0.25 to 20, in particular 0.5 to 10 mg / kg body weight in the form of several, preferably 1 to 4 individual doses to achieve the desired result.
  • parenteral treatment similar or (especially in the case of intravenous administration of the active compounds) in the gel lower doses are used.
  • the optimum dosage and type of application of the active ingredients required in each case can easily be determined by a specialist based on his specialist knowledge.
  • the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other groups of medicaments, such as antacids, for example aluminum hydroxide, magnesium aluminate; Tranquillizers, such as benzodiazepines, for example dlazepam; Antispasmodics, e.g. Bietamiverin, Camylofin; Anticholinergics such as Oxyphencyclimine, phencarbamide; Local anesthetics, e.g. Tetracaine, procaine, and possibly also ferment, vitamins or amino acids.
  • antacids for example aluminum hydroxide, magnesium aluminate
  • Tranquillizers such as benzodiazepines, for example dlazepam
  • Antispasmodics e.g. Bietamiverin, Camylofin
  • Anticholinergics such as Oxyphencyclimine, phencarbamide
  • Local anesthetics e.g. Tetracaine
  • H 2 blockers for example cimetidine, ranltidine
  • peripheral anticholinergics for example pirenzepin, telenzepin, zolenzepin
  • gastrin antagonists should be emphasized in particular , with the aim of strengthening the main effect in an additive or superadditive sense and / or eliminating or reducing the side effects.
  • the ulcer provocation takes place in 24 hours fasted rats (female, 180-200 g, 4 animals per cage on a high grating)
  • the ED25 and ED50 denote those doses that reduce the mean lesion index or HCl secretion by 25% and 50% compared to the control.
  • the LD50 of all tested compounds is above 1000 mg / kg [p.o.] in the mouse.

Abstract

Des composés aminés ayant la formule (I), où les substituants ont la signification donnée dans la description de l'invention, et leurs sels sont de nouveaux composés ayant un effet marqué de protection de l'estomac.Amino compounds having the formula (I), where the substituents have the meaning given in the description of the invention, and their salts are new compounds having a marked stomach-protecting effect.

Description

Neue Aminoverbindungen. Verfahren zu ihrer Herstellung, ihre Anwendung und sie enthaltende ArzneimittelNew amino compounds. Process for their preparation, their application and medicinal products containing them
Anwendungsgebiet der ErfindungField of application of the invention
Die Erfindung betrifft neue Aminoverbindungen, Verfahren zu ihrer Herstellung, ihre Anwendung und sie enthaltende Arzneimittel. Die erfindungsgemãßen Verbindungen werden in der pharmazeutischen Industrie als Zwischenprodukte und zur Herstellung von Medikamenten verwendet.The invention relates to new amino compounds, processes for their preparation, their use and medicaments containing them. The compounds according to the invention are used in the pharmaceutical industry as intermediates and for the manufacture of medicaments.
Stand der TechnikState of the art
In der europäischen Patentanmeldung 0 005 123 werden substituierteEuropean patent application 0 005 123 substitutes
Pyridylsulfinylbenzimidazole beschrieben, die magensäuresekretionshemmende Eigenschaften besitzen sollen. - In der europäischen Patentanmeldung 0 074 3.1 wird die Verwendung einer Reihe von Benzimidazolderivaten zur Magensäuresekretionshemmung beschrieben. - In der deutschen Offenlegungsschrift 34 04 610 werden weitere Benzimidazolderivate als zellschützende Mittel für den Magen-Darmkanal und als Hemmittel für die Magensäuresekretion bei Säugetieren beschrieben.Pyridylsulfinylbenzimidazole described that are said to have gastric acid secretion-inhibiting properties. - The European patent application 0 074 3.1 describes the use of a number of benzimidazole derivatives for inhibiting gastric acid secretion. - The German Offenlegungsschrift 34 04 610 describes further benzimidazole derivatives as cell-protecting agents for the gastrointestinal tract and as inhibitors for gastric acid secretion in mammals.
Es wurde nun überraschenderweise gefunden, daß die unten näher beschriebenen Aminoverbindungen interessante und unerwartete Eigenschaften aufweisen, durch die sie sich in vorteilhafter Weise von den bekannten Verbindungen unterscheiden.It has now surprisingly been found that the amino compounds described in more detail below have interesting and unexpected properties which distinguish them from the known compounds in an advantageous manner.
Beschreibung der ErfindungDescription of the invention
Gegenstand der Erfindung sind neue Aminoverbindungen der Formel IThe invention relates to new amino compounds of the formula I.
worin R1 , R2, R3 und R4 an beliebigen Positionen im Benzoteil des Benzimidazols stehen können und worinwherein R1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and where
R1 Wasserstoff oder C1-C6-Alkyl bedeutet,R1 is hydrogen or C 1 -C 6 alkyl,
R2 Wasserstoff, Cyan, Nitro, Halogen, Trifluormethyl, C1-C6-Alkyl, C1-C4-Alkoxy, C1-C4-Alkoxy-C1-C4-alkyl, C1-C2-Alkylendloxy-C1-C4alkyl, Hydroxy-C1-C4-alkyl, Cyan-C1-C4-alkoxy, C1-C4-Alkoxy-C1-C4alkoxy, C1-C6-Alkylcarbonyl, C1-C4-Alkoxycarbonyl, Phenyl, Phenoxy, Phenoxy-C1-C4-alkyl, Phenoxy-C1-C4-alkoxy, Phen-C1-C4alkyl, Phen-C1-C4-alkoxy oder Benzoyl bedeutet, R3 Wasserstoff, C1-C6-Alkyl, C1-C6-Alkoxy, ganz oder überwiegend durch Fluor substituiertes C1-C4-Alkoxy , Chlordifluormethoxy, 2-Chlor-1, 1 ,2-trifluorethoxy oder gemeinsam mit R4 ganz oder teilweise durch Fluor substituiertes C1-C2-Alkylendioxy oder Chlortrifluorethylendioxy bedeutet, R4 ganz oder überwiegend durch Fluor substituiertes C1-C4-Alkoxy,R2 is hydrogen, cyano, nitro, halogen, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkyl, C 1 -C 2 alkylendloxy -C 1 -C 4 alkyl, hydroxy-C 1 -C 4 alkyl, cyano-C 1 -C 4 alkoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkoxy, C 1 -C 6 alkylcarbonyl , C 1 -C 4 alkoxycarbonyl, phenyl, phenoxy, phenoxy-C 1 -C 4 alkyl, phenoxy-C 1 -C 4 alkoxy, phen-C 1 -C 4 alkyl, phen-C 1 -C 4 - alkoxy or benzoyl means R3 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, completely or predominantly fluorine-substituted C 1 -C 4 -alkoxy, chlorodifluoromethoxy, 2-chloro-1, 1, 2- trifluoroethoxy or together with R4 completely or partially fluorine-substituted C 1 -C 2 -alkylenedioxy or chlorotrifluoroethylene-dioxy, R4 is completely or predominantly fluorine-substituted C 1 -C 4 -alkoxy,
Chlordifluormethoxy, 2-Chlor-1,1,2-trifluorethoxy oder gemeinsam mit R3 ganz oder teilweise durch Fluor substituiertes C1-C2-Alkylendioxy oder Chlortrifluorethylendioxy bedeutet,Chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R3 completely or partially fluorine-substituted C 1 -C 2 -alkylenedioxy or chlorotrifluoroethylenedioxy,
R5 Wasserstoff oder eine unter physiologischen Bedingungen leicht abspaltbare Gruppe bedeutet,R5 denotes hydrogen or a group which can easily be split off under physiological conditions,
R6 Wasserstoff oder C1-C4-Alkyl bedeutet,R6 represents hydrogen or C 1 -C 4 alkyl,
R7 Wasserstoff, C1-C4-Alkyl, C1-C4-Alkoxy oder gemeinsam mit R8a C2-C3-Alkylen bedeutet,R7 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or together with R8a is C 2 -C 3 -alkylene,
R8a Wasserstoff, C1-C4-Alkyl, C3-C4-Alkenyl, gemeinsam mit R7 C2-C3Alkylen, gemeinsam mit R9 C2-C3-Alkylen oder gemeinsam mit R8b gegebenenfalls durch Sauerstoff unterbrochenes C4-C6-Alkylen bedeutet,R8a is hydrogen, C 1 -C 4 -alkyl, C 3 -C 4 -alkenyl, together with R7 C 2 -C 3 alkylene, together with R9 C 2 -C 3 -alkylene or together with R8b optionally C 4 - interrupted by oxygen C 6 alkylene means
R8b Wasserstoff, C1-C4-Alkyl, C3-C4-Alkenyl, C1-C4-Alkylcarbonyl oder gemeinsam mit RBa gegebenenfalls durch Sauerstoff unterbrochenes C4-C6-Alkylen bedeutet,R8b is hydrogen, C 1 -C 4 -alkyl, C 3 -C 4 -alkenyl, C 1 -C 4 -alkylcarbonyl or together with RBa C 4 -C 6 -alkylene optionally interrupted by oxygen,
R9 Wasserstoff, C1-C4-Alkyl, C1-C4-Alkoxy oder gemeinsam mit R8a C2-C3-Alkylen bedeutet,R9 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or together with R8a is C 2 -C 3 -alkylene,
R10 Wasserstoff oder C1-C4-Alkyl bedeutet und n die Zahlen 0 oder 1 darstellt, und die Salze dieser Verbindungen.R10 represents hydrogen or C 1 -C 4 alkyl and n represents the numbers 0 or 1, and the salts of these compounds.
Halogen im Sinne der vorliegenden Erfindung ist Brom, Chlor und Fluor. C1-C6-Alkyl steht für geradkettige, verzweigte oder cyclische Alkylreste. Geradkettige Alkylreste sind der Hexyl-, Pentyl-, Butyl-, Propyl-, Ethyl-, und insbesondere der Methylrest. Verzweigte Alkylreste sind beispielsweise der Neopentyl-, 1-Butyl-, sec.-Butyl-, t-Butyl- und der Isopropylrest. Als cyclische Alkylreste seien der Cyclopropyl-, Cyclobutyl-, Cyclopentyl- und der Cyclohexylrest genannt.Halogen in the sense of the present invention is bromine, chlorine and fluorine. C 1 -C 6 alkyl represents straight-chain, branched or cyclic alkyl radicals. Straight-chain alkyl radicals are the hexyl, pentyl, butyl, propyl, ethyl, and especially the methyl radical. Branched alkyl radicals are, for example, the neopentyl, 1-butyl, sec-butyl, t-butyl and the isopropyl radical. The cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals may be mentioned as cyclic alkyl radicals.
C1-C6-Alkoxy steht für geradkettige oder verzweigte Alkoxyreste. Beispielsweise seien genannt der Hexyloxy-, Neopentyloxy-, Butoxy-, 1-Butoxy-, sec. -Butoxy-, t-Butoxy-, Propoxy-, Isopropoxy-, Ethoxy- und insbesondere der Methoxyrest.C 1 -C 6 alkoxy represents straight-chain or branched alkoxy radicals. Examples include the hexyloxy, neopentyloxy, butoxy, 1-butoxy, sec-butoxy, t-butoxy, propoxy, isopropoxy, ethoxy and especially the methoxy radical.
C1-C4-Alkoxy steht für geradkettige oder verzweigte Alkoxyreste; beispielsweise seien genannt der Butoxy-, i-Butoxy-, sec. -Butoxy-, t-Butoxy-, Propoxy-, Isopropoxy-, Ethoxy- und insbesondere der Methoxyrest.C 1 -C 4 alkoxy represents straight-chain or branched alkoxy radicals; Examples include the butoxy, i-butoxy, sec. butoxy, t-butoxy, propoxy, isopropoxy, ethoxy and in particular the methoxy radical.
C1-C4-Alkyl steht für geradkettige oder verzweigte Alkylreste; beispielsweise seien der Butyl-, i-Butyl-, sec.-Butyl-, t-Butyl-, Propyl-, Isopropyl-, Ethyl- und insbesondere der Methylrest genannt.C 1 -C 4 alkyl represents straight-chain or branched alkyl radicals; For example, the butyl, i-butyl, sec-butyl, t-butyl, propyl, isopropyl, ethyl and especially the methyl radical may be mentioned.
C1-C4-Alkoxy-C1-C4-alkyl steht für C1-C4-Alkyl, das durch C1-C4-Alkoxy substituiert ist. Beispielsweise seien der Ethoxymethyl-, Propoxy- butyl-, Methoxymethyl und insbesondere der Methoxyethylrest genannt.C 1 -C 4 alkoxy-C 1 -C 4 alkyl represents C 1 -C 4 alkyl which is substituted by C 1 -C 4 alkoxy. Examples include the ethoxymethyl, propoxybutyl, methoxymethyl and in particular the methoxyethyl radical.
C1-C2-Alkylendioxy-C1-C4-alkyl steht für C1-C4-Alkyl, das durch einen Alkylendioxyrest substituiert ist. Beispielsweise sei der Ethylendioxy- methylrest genannt.C 1 -C 2 -alkylenedioxy-C 1 -C 4 -alkyl represents C 1 -C 4 -alkyl which is substituted by an alkylenedioxy radical. For example, the ethylenedioxymethyl radical may be mentioned.
Hydroxy-C1-C4-alkyl steht für C1-C4-Alkyl, das durch einen Hydroxyrest substituiert ist. Beispielsweise seien der 3-Hydroxybutyl-, 2-Hydroxy- isopropyl-, 2-Hydroxyethyl- und insbesondere der Hydroxymethylrest genannt.Hydroxy-C 1 -C 4 alkyl represents C 1 -C 4 alkyl which is substituted by a hydroxy radical. For example, the 3-hydroxybutyl, 2-hydroxyisopropyl, 2-hydroxyethyl and especially the hydroxymethyl radical may be mentioned.
Cyan-C1-C4-alkoxy steht für C1-C4-Alkoxy, das durch einen Cyanrest substituiert ist. Beispielsweise sei der Cyanomethoxyrest genannt.Cyan-C 1 -C 4 alkoxy stands for C 1 -C 4 alkoxy which is substituted by a cyan radical. For example, the cyanomethoxy radical may be mentioned.
C1-C4-Alkoxy-C1-C4-alkoxy steht für C1-C4-Alkoxy , das durch C1-C4- Alkoxy substituiert ist. Beispielsweise seien der Ethoxyethoxy-, Methoxypropoxy-, Ethoxymethoxy- und insbesondere der Methoxyethoxyrest genannt.C 1 -C 4 alkoxy-C 1 -C 4 alkoxy represents C 1 -C 4 alkoxy, which is replaced by C 1 -C 4 - Alkoxy is substituted. Examples include the ethoxyethoxy, methoxypropoxy, ethoxymethoxy and in particular the methoxyethoxy radical.
C1-C6-Alkylcarbonyl steht für an eine Carbonylgruppe gebundenes C1-C6- Alkyl. Beispielsweise seien der Propionyl-, Butyryl- i-Butyryl- und insbesondere der Cyclopropylcarbonyl- und der Acetylrest genannt.C 1 -C 6 alkylcarbonyl represents C 1 -C 6 alkyl bonded to a carbonyl group. For example, the propionyl, butyryl, i-butyryl and in particular the cyclopropylcarbonyl and acetyl radicals may be mentioned.
C1-C4-Alkoxycarbonyl steht für an eine Carbonylgruppe gebundenes C1-C4- Alkoxy. Beispielsweise seien der Ethoxycarbonyl- und der Methoxycar- bonylrest genannt.C 1 -C 4 alkoxycarbonyl represents a carbonyl group bonded to C 1 -C 4 - alkoxy. Examples include the ethoxycarbonyl and methoxycarbonyl radicals.
Phenoxy-C1-C4-alkyl steht für C1-C4-Alkyl, das durch einen Phenoxyrest substituiert ist. Beispielsweise seien der Phenoxypropyl- und der Phenoxyethylrest genannt.Phenoxy-C 1 -C 4 alkyl stands for C 1 -C 4 alkyl which is substituted by a phenoxy radical. For example, the phenoxypropyl and the phenoxyethyl radical may be mentioned.
Phenoxy-C1-C4-alkoxy steht für C1-C4-Alkoxy, das durch einen Phenoxyrest substituiert ist. Beispielsweise seien der Phenoxyethoxy- und der Phenoxypropoxyrest genannt.Phenoxy-C 1 -C 4 alkoxy stands for C 1 -C 4 alkoxy which is substituted by a phenoxy radical. For example, the phenoxyethoxy and the phenoxypropoxy radical may be mentioned.
Phen-C1-C4-alkyl steht für C1-C4-Alkyl, das durch einen Phenylrest substituiert ist. Beispielsweise seien der Phenethyl und insbesondere der Benzylrest genannt.Phen-C 1 -C 4 alkyl represents C 1 -C 4 alkyl which is substituted by a phenyl radical. Examples include the phenethyl and especially the benzyl radical.
Phen-C1-C4-alkoxy steht für C1-C4-Alkoxy, das durch einen Phenylrest substituiert ist. Beispielsweise seien der 2-Phenyl-ethoxy- und der Benzyloxyrest genannt.Phen-C 1 -C 4 alkoxy stands for C 1 -C 4 alkoxy which is substituted by a phenyl radical. Examples include the 2-phenyl-ethoxy and the benzyloxy radical.
Als ganz oder überwiegend durch Fluor substituiertes C1-C4-Alkoxy seien beispielsweise der 1 ,1 ,2-Trifluorethoxy-, der Perfluorpropoxy-, der Perfluorethoxy- und insbesondere der 1,1,2,2-Tetrafluorethoxy-, der Trifluormethoxy-, der 2,2,2-Trifluorethoxy- und der Oifluormethoxyrest genannt.Examples of 1, 1, 2-trifluoroethoxy, perfluoropropoxy, perfluoroethoxy and, in particular, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, and the like as completely or predominantly substituted by fluorine are C 1 -C 4 alkoxy. , the 2,2,2-trifluoroethoxy and the Oifluormethoxyrest called.
Als ganz oder teilweise durch Fluor substituiertes C1-C2-Alkylendioxy seien beispielsweise der 1,1-Difluorethylendioxy- (-O-CF2-CH2-O-), der 1,1,2,2-Tetrafluorethylendioxy- (-O-CF2-CF2-O-) und insbesondere der Difluormethylendioxy- (-O-CF2-O-) und der 1,1,2-Trifluorethylendloxy- rest (-O-CF2-CHF-O-) genannt.Examples of the completely or partially substituted by fluorine-substituted C 1 -C 2 -alkylenedioxy are 1,1-difluoroethylenedioxy- (-O-CF 2 -CH 2 -O-), 1,1,2,2-tetrafluoroethylenedioxy- (- O-CF 2 -CF 2 -O-) and in particular the difluoromethylene dioxy- (-O-CF 2 -O-) and the 1,1,2-trifluoroethyleneendloxy- rest (-O-CF 2 -CHF-O-).
Eine unter physiologischen Bedingungen leicht abspaltbare Gruppe R5 ist ein Substituent, der durch - gegebenenfalls enzymatisch katalysierte Hydrolyse vom Stickstoffatom unter Ausbildung einer N-H-Bindung abgetrennt wird, wobei er selbst - unter Anbindung einer Hydroxylgruppe - in eine physiologisch unbedenkliche und insbesondere pharmakologisch vertrSgliche Verbindung umgewandelt wird. Als abspaltbare Gruppen R5 seien insbesondere alle Arten von substituierten Carbonylgruppen genannt, wie die Alkylcarbonyl-, Arylcarbonyl-, Aralkylcarbonyl-,A group R5, which can easily be split off under physiological conditions, is a substituent which is separated from the nitrogen atom by, if appropriate, enzymatically catalyzed hydrolysis to form an NH bond, whereby it itself - with the attachment of a hydroxyl group - is converted into a physiologically acceptable and in particular pharmacologically compatible compound . All types of substituted carbonyl groups, such as the alkylcarbonyl, arylcarbonyl, aralkylcarbonyl,
Alkoxycarbonyl-, Aryloxycarbonyl-, Aralkoxycarbonyl- oder die gegebenenfalls substituierte Carbamoylgruppe. Beispielsweise seien die Methoxycarbonyl-, t-Butoxycarbonyl-, Benzoyl-, Phenylcarbamoyl- und die Dimethylcarbamoylgruppe genannt.Alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl or the optionally substituted carbamoyl group. Examples include the methoxycarbonyl, t-butoxycarbonyl, benzoyl, phenylcarbamoyl and dimethylcarbamoyl groups.
C2-C3-Alkylen, das gemeinsam von R8a und R7 oder R8a und R9 gebildet wird, steht für Ethylen oder Propylen.C 2 -C 3 alkylene, which is formed jointly by R8a and R7 or R8a and R9, stands for ethylene or propylene.
C3-C4-Alkenyl steht für den But-2-enyl-, den But-3-enyl- und insbesondere für den Allylrest.C 3 -C 4 alkenyl represents the but-2-enyl, the but-3-enyl and in particular the allyl radical.
Gegebenenfalls durch Sauerstoff unterbrochenes C4-C6-Alkylen steht für -(CH2)4-, -(CH2)5-, -(CH2)6- oder -(CH2) 2-O-(Ch2) 2-, so daß sich für die Reste R8a und R8b gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, ein Pyrrolidlno-, Piperidino-, Perhydroazepino- oder Morpholinorest ergibt.C 4 -C 6 alkylene which may be interrupted by oxygen represents - (CH 2 ) 4 -, - (CH 2 ) 5 -, - (CH 2 ) 6 - or - (CH 2 ) 2 -O- (Ch 2 ) 2 -, so that for the radicals R8a and R8b together with the nitrogen atom to which they are attached there is a pyrrolidlno, piperidino, perhydroazepino or morpholino radical.
C1-C4-Alkylcarbonyl steht für an eine Carbonylgruppe gebundenes C1-C4- Alkyl. Beispielsweise seien der Proplonyl-, Butyryl- und insbesondere der Acetylrest genannt.C 1 -C 4 alkylcarbonyl represents C 1 -C 4 alkyl bonded to a carbonyl group. For example, the proponyl, butyryl and especially the acetyl radical may be mentioned.
Als Salze kommen für Verbindungen der Formel I, in denen n die Zahl 0 bedeutet (Sulfide), bevorzugt alle Säureaddltionssalze in Betracht. Besonders erwähnt seien die pharmakologisch verträglichen Salze der in der Galenik üblicherweise verwendeten anorganischen und organischen Säuren. Pharmakologisch unverträgliche Salze, die beispielsweise bei der Herstellung der erfindungsgemäBen Verbindungen im industriellen Maßstab als Verfahrensprodukte zunächst anfallen können, werden durch dem Fachmann bekannte Verfahren In pharmakologisch vertrSgliche Salze übergeführt. Als solche eignen sich beispielsweise wasserlösliche und wasserunlösliche Slureadditionssalze, wie das Hydrochlorld, Hydro- bromid, Hydroiodid, Phosphat, Nitrat, Sulfat, Acetat, Cltrat, Gluconat, Benzoat, Hibenzat, Fendizoat, Butyrat, Sulfosallcylat, Maleat, Laurat, Malat, Fumarat, Succinat, Oxalat, Tartrat, Amsonat, Embonat, Metembonat, Stearat, Tosilat, 2-Hydroxy-3-naphthoat, 3-Hydroxy-2-naphthoat oder Mesilat.Suitable salts for compounds of the formula I in which n is the number 0 (sulfides), are preferably all acid addition salts. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids commonly used in galenics. Pharmacologically incompatible salts, which can initially be obtained as process products, for example in the preparation of the compounds according to the invention, are characterized by Methods known to the person skilled in the art converted into pharmacologically acceptable salts. Suitable as such are, for example, water-soluble and water-insoluble slurry addition salts, such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, cltrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosallcylate, maleate, laurate, malate, fumarate Succinate, oxalate, tartrate, amsonate, embonate, metembonate, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate.
Für Verbindungen der Formel I, in denen n die Zahl 1 bedeutet (Sulf- oxide), kommen als Salze bevorzugt basische Salze in Betracht, insbesondere pharmakologisch vertrSgliche Salze mit in der Galenik üblicherweise verwendeten anorganischen und organischen Basen. Als Beispiele für basische Salze seien Lithium-, Natrium-, Kalium-, Calcium-, Aluminium-, Magnesium-, Titan-, Ammonium- oder Guanidiniumsalze er- wShnt.For compounds of the formula I in which n is 1 (sulfoxides), the preferred salts are basic salts, in particular pharmacologically compatible salts with inorganic and organic bases commonly used in galenics. Lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium or guanidinium salts may be mentioned as examples of basic salts.
Wenn R3 und R4 gemeinsam ganz oder teilweise durch Fluor substituiertes C1-C2-Alkylendioxy oder Chlortrifluorethylendloxy bedeuten, so sind die Substituenten R3 und R4 in Nachbarpositionen am Benzoteil des Benzimi- dazolringes gebunden.If R3 and R4 together mean completely or partially substituted by fluorine-substituted C 1 -C 2 -alkylenedioxy or chlorotrifluoroethylenedloxy, the substituents R3 and R4 are bonded in neighboring positions on the benzo part of the benzimidazole ring.
Eine Ausgestaltung (Ausgestaltung a) der Erfindung sind Verbindungen der Formel I, worin R7 und R9 Wasserstoff bedeuten und R1, R2, R3, R4, R5, R6, R8a, R8b, R10 und n die eingangs angegebenen Bedeutungen haben, und ihre Salze.One embodiment (embodiment a) of the invention are compounds of the formula I in which R7 and R9 are hydrogen and R1, R2, R3, R4, R5, R6, R8a, R8b, R10 and n have the meanings given above, and their salts.
Eine weitere Ausgestaltung (Ausgestaltung b) der Erfindung sind Verbindungen der Formel I, worin R7 C1-C4-Alkyl bedeutet, R9 Wasserstoff bedeutet und R1, R2, R3, R4, R5, R6, R8a, R8b, R10 und n die eingangs angegebenen Bedeutungen haben, und ihre Salze.A further embodiment (embodiment b) of the invention are compounds of the formula I in which R7 is C 1 -C 4 -alkyl, R9 is hydrogen and R1, R2, R3, R4, R5, R6, R8a, R8b, R10 and n the have meanings given above, and their salts.
Hervorzuhebende erfindungsgemäße Verbindungen sind solche, in denenCompounds according to the invention which are to be emphasized are those in which
R1 Wasserstoff oder C1-C4-Alkyl bedeutet,R1 is hydrogen or C 1 -C 4 alkyl,
R2 Wasserstoff, Halogen, Trifluormethyl, C1-C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkoxy-C1-C4-alkyl, Hydroxy-C1-C4-alkyl, C1-C4-Alkoxy-C1-C4- alkoxy, C1-C4-Alkylcarbonyl, C1-C4-Alkoxycarbonyl, Phenyl, Phenoxy, Phenoxy-C1-C4-alkyl, Phenoxy-C1-C4-alkoxy, Phen-C1-C4-alkyl, Phen-C1-C4-alkoxy oder Benzoyl bedeutet,R2 is hydrogen, halogen, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkyl, hydroxy-C 1 -C 4 alkyl, C 1 -C 4 alkoxy-C 1 -C 4 alkoxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, phenyl, Phenoxy, phenoxy-C 1 -C 4 -alkyl, phenoxy-C 1 -C 4 -alkoxy, phen-C 1 -C 4 -alkyl, phen-C 1 -C 4 -alkoxy or benzoyl,
R3 Wasserstoff, C1-C4-Alkyl, C1-C4-Alkoxy, ganz oder überwiegend durch Fluor substituiertes C1-C4-Alkoxy, Chlordifluormethoxy, 2-Chlor-1,1,2-trifluorethoxy oder gemeinsam mit R4 ganz oder teilweise durch Fluor substituiertes C1-C2-Alkylendioxy oder Chlortrifluorethylendloxy bedeutet,R3 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, completely or predominantly substituted by fluorine-substituted C 1 -C 4 -alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R4 C 1 -C 2 -alkylenedioxy or chlorotrifluoroethylenedloxy which is wholly or partly substituted by fluorine,
R4 ganz oder überwiegend durch Fluor substituiertes C1-C4-Alkoxy, Chlordifluormethoxy, 2-Chlor-1,1,2-trifluorethoxy oder gemeinsam mit R3 ganz oder teilweise durch Fluor substituiertes C1-C2-Alky- lendioxy oder Chlortrifluorethylendloxy bedeutet,R4 is completely or predominantly substituted by fluorine-substituted C 1 -C 4 -alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R3 completely or partially substituted by fluorine-substituted C 1 -C 2 -alkylene dioxy or chlorotrifluoroethylene doxy ,
R5 Wasserstoff bedeutet,R5 means hydrogen
R6 Wasserstoff oder C1-C4-Alkyl bedeutet,R6 represents hydrogen or C 1 -C 4 alkyl,
R8 Wasserstoff, C1-C4-Alkyl, C1-C4-Alkoxy oder gemeinsam mit R8a C2-C3-Alkylen bedeutet,R8 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or together with R8a is C 2 -C 3 -alkylene,
R8a Wasserstoff, C1-C4-Alkyl, gemeinsam mit R7 C2-C3-Alkylen, gemeinsam mit R9 C2-C3-Alkylen oder gemeinsam mit R8b gegebenenfalls durch Sauerstoff unterbrochenes C4-C6-Alkylen bedeutet,R8a is hydrogen, C 1 -C 4 alkyl, together with R7 is C 2 -C 3 alkylene, together with R9 is C 2 -C 3 alkylene or together with R8b is C 4 -C 6 alkylene which is optionally interrupted by oxygen,
R8b Wasserstoff, C1-C4-Alkyl, C1-C4-Alkylcarbonyl oder gemeinsam mit R8a gegebenenfalls durch Sauerstoff unterbrochenes C4-C6-Alkylen bedeutet,R8b is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylcarbonyl or, together with R8a, C 4 -C 6 alkylene which is optionally interrupted by oxygen,
R9 Wasserstoff, C1-C4-Alkyl, C1-C4-Alkoxy oder gemeinsam mit R8a C2-C3-Alkylen bedeutet,R9 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or together with R8a is C 2 -C 3 -alkylene,
R10 Wasserstoff oder C1-C4-Alkyl bedeutet und n die Zahlen 0 oder 1 darstellt, und die Salze dieser Verbindungen.R10 represents hydrogen or C 1 -C 4 alkyl and n represents the numbers 0 or 1, and the salts of these compounds.
Eine Ausgestaltung (Ausgestaltung a') der hervorzuhebenden Verbindungen sind solche der Formel I, worin R7 und R9 Wasserstoff bedeuten und R1, R2, R3, R4, R5, R6, R8a, R8b, R10 und n die für die hervorzuhebenden Verbindungen angegebenen Bedeutungen haben, und ihre Salze.An embodiment (embodiment a ') of the compounds to be emphasized are those of the formula I in which R7 and R9 are hydrogen and R1, R2, R3, R4, R5, R6, R8a, R8b, R10 and n have the meanings given for the compounds to be emphasized , and their salts.
Eine weitere Ausgestaltung (Ausgestaltung b') der hervorzuhebenden Verbindungen sind solche der Formel I, worin R7 C1-C4-Alkyl bedeutet, R9 Wasserstoff bedeutet und R1, R2, R3, R4, R5, R6, R8a, R8b, R10 und n die für die hervorzuhebenden Verbindungen angegebenen Bedeutungen haben, und ihre Salze. Bevorzugte erfindungsgemäße Verbindungen sind solche, in denenA further embodiment (embodiment b ') of the compounds to be emphasized are those of the formula I in which R7 is C 1 -C 4 -alkyl, R9 is hydrogen and R1, R2, R3, R4, R5, R6, R8a, R8b, R10 and n have the meanings given for the compounds to be emphasized, and their salts. Preferred compounds according to the invention are those in which
R1 Wasserstoff, Methyl oder Ethyl bedeutet, R2 Wasserstoff, Chlor, Fluor, Trifluormethyl, Methyl, Ethyl, Methoxy, Ethoxy, Acetyl, Methoxycarbonyl oder Ethoxycarbonyl bedeutet, R3 Wasserstoff, Methyl, Ethyl, Methoxy, Ethoxy, 1,1,2,2-Tetrafluor- ethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy, Difluormethoxy oder gemeinsam mit R4 Difluormethylendloxy, 1,1,2-Trifluorethylendioxy oder 1-Chlor-1,2,2-trifluorethylendioxy bedeutet,R1 is hydrogen, methyl or ethyl, R2 is hydrogen, chlorine, fluorine, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, acetyl, methoxycarbonyl or ethoxycarbonyl, R3 is hydrogen, methyl, ethyl, methoxy, ethoxy, 1,1,2,2 -Tetrafluoro-ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy or together with R4 means difluoromethyleneendloxy, 1,1,2-trifluoroethylene dioxy or 1-chloro-1,2,2-trifluoroethylene dioxy,
R4 1,1,2,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trlfluorethoxy, Difluormethoxy oder gemeinsam mit R3 Difluormethylendloxy, 1,1,2- Trifluorethylendioxy oder 1-Chlor-1,2,2-trifluorethylendioxy bedeutet, R5 Wasserstoff bedeutet,R4 denotes 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trlfluoroethoxy, difluoromethoxy or together with R3 difluoromethylene-dioxy, 1,1,2-trifluoroethylene-dioxy or 1-chloro-1,2,2-trifluoroethylene-dioxy, R5 Hydrogen means
RB Wasserstoff, Methyl oder Ethyl bedeutet,RB means hydrogen, methyl or ethyl,
R7 Wasserstoff, Methyl, Ethyl, Methoxy, Ethoxy oder gemeinsam mit R8aR7 is hydrogen, methyl, ethyl, methoxy, ethoxy or together with R8a
Ethylen oder Propylen bedeutet, R8a Wasserstoff, Methyl, Ethyl, gemeinsam mit R7 Ethylen oder Propylen, gemeinsam mit R9 Ethylen oder Propylen oder gemeinsam mit R8b und dem Stickstoffatom, woran beide gebunden sind, Pyrro- lidino, Piperidino oder Morpholino bedeutet, R8b Wasserstoff, Methyl, Ethyl, Acetyl oder gemeinsam mit R8a und dem Stickstoffatom, woran beide gebunden sind, Pyrrolidino, Piperidino oder Morpholino bedeutet,Ethylene or propylene means R8a is hydrogen, methyl, ethyl, together with R7 ethylene or propylene, together with R9 ethylene or propylene or together with R8b and the nitrogen atom, to which both are bound, pyrrolidino, piperidino or morpholino means R8b hydrogen, Methyl, ethyl, acetyl or together with R8a and the nitrogen atom, to which both are bound, means pyrrolidino, piperidino or morpholino,
R9 Wasserstoff, Methyl, Ethyl, Methoxy, Ethoxy oder gemeinsam mit R8aR9 is hydrogen, methyl, ethyl, methoxy, ethoxy or together with R8a
Ethylen oder Propylen bedeutet, R10 Wasserstoff, Methyl oder Ethyl bedeutet und n die Zahlen 0 oder 1 darstellt, und die Salze dieser Verbindungen.Ethylene or propylene means R10 means hydrogen, methyl or ethyl and n represents the numbers 0 or 1, and the salts of these compounds.
Eine Ausgestaltung (Ausgestaltung a'') der bevorzugten Verbindungen sind solche der Formel I, worin R7 und R9 Wasserstoff bedeuten und Rl, R2, R3, R4, R5, R6, R8a, R8b, R10 und n die für die bevorzugten Verbindungen angegebenen Bedeutungen haben, und ihre Salze.An embodiment (embodiment a ″) of the preferred compounds are those of the formula I in which R7 and R9 are hydrogen and Rl, R2, R3, R4, R5, R6, R8a, R8b, R10 and n are the meanings given for the preferred compounds and their salts.
Eine weitere Ausgestaltung (Ausgestaltung b'') der bevorzugten Verbindungen sind solche der Formel I, worin R7 Methyl oder Ethyl bedeutet, R9 Wasserstoff bedeutet und R1, 12, R3, R4, R5, R6, R8a, R8b, R10 und n die für die bevorzugten Verbindungen angegebenen Bedeutungen haben, und ihre Salze.A further embodiment (embodiment b '') of the preferred compounds are those of the formula I in which R7 is methyl or ethyl, R9 is hydrogen and R1, 12, R3, R4, R5, R6, R8a, R8b, R10 and n have the meanings given for the preferred compounds, and their salts.
Weiterhin sind solche Verbindungen bevorzugt, in denen R6 und Rio Wasserstoff bedeuten, und ihre Salze.Also preferred are those compounds in which R6 and Rio are hydrogen, and their salts.
Besonders bevorzugte erfindungsgemäße Verbindungen sind solche, in denen R1 Wasserstoff bedeutet,Particularly preferred compounds according to the invention are those in which R1 is hydrogen,
R2 Wasserstoff bedeutet,R2 means hydrogen
R3 Wasserstoff oder gemeinsam mit R4 Difluormethylendloxy bedeutet,R3 is hydrogen or together with R4 difluoromethyleneendloxy,
R4 1,1,2,2-Tetrafluorethoxy, Dlfluormethoxy oder gemeinsam mit R3 Difluormethylendloxy bedeutet, R5 Wasserstoff bedeutet,R4 denotes 1,1,2,2-tetrafluoroethoxy, Dlfluormethoxy or together with R3 Difluormethylenendloxy, R5 means hydrogen,
R6 Wasserstoff bedeutet,R6 means hydrogen,
R7 Waserstoff oder Methyl bedeutet,R7 means hydrogen or methyl,
R8a Methyl oder gemeinsam mit R8b und dem Stickstoffatom, woran beide gebunden sind, Pyrrolidino oder Morpholino bedeutet, R8b Methyl oder gemeinsam mit R8a und dem Stickstoffatom, woran beide gebunden sind, Pyrrolidino oder Morpholino bedeutet,R8a is methyl or together with R8b and the nitrogen atom, to which both are bound, means pyrrolidino or morpholino, R8b is methyl or together with R8a and the nitrogen atom, to which both are bonded, means pyrrolidino or morpholino,
R9 Wasserstoff bedeutet,R9 means hydrogen,
R10 Wasserstoff bedeutet und n die Zahlen 0 oder 1 darstellt, und die Salze dieser Verbindungen.R10 represents hydrogen and n represents the numbers 0 or 1, and the salts of these compounds.
Bei den bevorzugten und besonders bevorzugten erfindungsgemäßen Verbindungen bzw. bei den bevorzugten Verbindungen der Ausgestaltungen a'' und b'' sind die Substituenten R3 und R4 insbesondere in 5- und 6-Position des Benzimidazols.In the preferred and particularly preferred compounds according to the invention or in the preferred compounds of the embodiments a ″ and b ″, the substituents R3 and R4 are in particular in the 5- and 6-position of the benzimidazole.
Bei den Verbindungen der Formel I, worin R5 Wasserstoff bedeutet, ist - bedingt durch die Tautomerie im Imidazolring - im Benzimidazol die 4-Position mit der 7-Position, und die 5-Position mit der 6-Position identisch.In the compounds of the formula I in which R5 is hydrogen, the 4-position with the 7-position and the 5-position with the 6-position are identical in the benzimidazole due to the tautomerism in the imidazole ring.
Ein weiterer Gegenstand der Erfindung ist ein Verfahren zur Herstellung der Verbindungen der Formel I, worin R1, R2, R3 , R4, R5, R6, R7, R8a, R8b, R9, R10 und n die oben angegebenen Bedeutungen haben, und ihrer Salze.The invention further relates to a process for the preparation of the compounds of the formula I in which R1, R2, R3, R4, R5, R6, R7, R8a, R8b, R9, R10 and n have the meanings given above, and their salts.
Das Verfahren ist dadurch gekennzeichnet, daß manThe process is characterized in that
a) Mercaptobenzlmidazole der Formel II mit 2-Pyridylverbindungen III,a) mercaptobenzlmidazoles of the formula II with 2-pyridyl compounds III,
oder b) Benzimidazole der Formel IV mit Mercaptopicolinen V, or b) benzimidazoles of the formula IV with mercaptopicolins V,
oder c) o-Phenylendiamine der Formel VI mit Ameisensäurederivaten VII or c) o-phenylenediamines of the formula VI with formic acid derivatives VII
umsetzt und (falls Verbindungen der Formel I mit n=l die gewünschten Endprodukte sind) anschlie8end die nach a), b) oder c) erhaltenen 2-Benzimidazolyl-2-pyridylmethyl-sulfide der Formel VIII (=Verbindungen der Formel I mit n=0) and (if compounds of the formula I with n = 1 are the desired end products) then the 2-benzimidazolyl-2-pyridylmethylsulphides of the formula VIII (= compounds of the formula I with n =) obtained according to a), b) or c) 0)
oxidlert und/oder gewünschtenfalls in die Salze überführt, oder daß manoxidized and / or, if desired, converted into the salts, or that
d) Benzimidazole der Formel IX mit Pyridinderivaten Xd) Benzimidazoles of the formula IX with pyridine derivatives X
oder e) Sulfinyldefivate der Formel XI mit 2-Pyridylverbindungenn XII or e) sulfinyl derivatives of the formula XI with 2-pyridyl compounds XII
umsetzt und gewünschtenfalls anschlleßend in die Salze Oberführt, oder implemented and, if desired, subsequently introduced into the salts, or
f) - falls Verbindungen der Formel I, worin R5 eine unter physiologischen Bedingungen leicht abspaltbare Gruppe darstellt, die herzustellenden Verfahrensprodukte sind - daß man Verbindungen der Formel I, worin R5 Wasserstoff bedeutet, mit Verbindungen der Formel RS'-Y' (XIII), worin R5' die gewünschte, unter physiologischen Bedingungen leicht abspaltbare Gruppe oder gemeinsam mit Y' ihr Vorläufer ist, umsetzt und gewünschtenfalls anschlleßend in die Salze überführt, oderf) - if compounds of the formula I in which R5 is a group which can easily be split off under physiological conditions are the process products to be prepared - that compounds of the formula I in which R5 is hydrogen are reacted with compounds of the formula RS'-Y '(XIII), in which R5 'is the desired group which can easily be split off under physiological conditions or, together with Y', is its precursor and, if desired, is subsequently converted into the salts, or
g) - falls Verbindungen der Formel I, worin R5 Wasserstoff bedeutet, die herzustellenden Verfahrensprodukte sind - daß man Verbindungen der Formel I, worin R5 eine unter physiologischen Bedingungen leicht abspaltbare Gruppe darstellt, solvolysiert, und die erhaltenen Produkte gewünschtenfalls in die Salze überführt, oderg) - if compounds of the formula I, in which R5 is hydrogen, are the process products to be prepared - that compounds of the formula I, in which R5 is a group which can be readily split off under physiological conditions, are solvolysed and the products obtained, if desired, converted into the salts, or
h) - falls Verbindungen der Formel I, worin R6 C1-C6-Alkyl bedeutet, die herzustellenden Verfahrensprodukte sind - daß man Verbindungen der Formel I, worin R6 Wasserstoff bedeutet, mit Verbindungen der Formel R6-Y" (XIV), worin RB C1-C6-Alkyl bedeutet, alkyliert und gewünschtenfalls anschließend in die Salze überführt,h) - if compounds of the formula I in which R6 is C 1 -C 6 -alkyl are the process products to be prepared - that compounds of the formula I in which R6 is hydrogen with compounds of the formula R6-Y "(XIV) in which RB denotes C 1 -C 6 alkyl, alkylated and, if desired, subsequently converted into the salts,
wobei Y, Y", Z, Z' und Z ' ' geeignete Abgangsgruppen darstellen, Y' eine Abgangs- bzw. Reaktivgruppe darstellt, M für ein Alkalimetallatom (Li, Na oder K) steht, M' für das Äquivalent eines Metallatoms steht und R1, R2, R3, R4, RS, RB, R7, R8a, R8b, R9, R10 und n (sofern nicht anders definiert) die oben angegebenen Bedeutungen haben.where Y, Y ", Z, Z 'and Z" represent suitable leaving groups, Y' represents a leaving or reactive group, M stands for an alkali metal atom (Li, Na or K), M 'stands for the equivalent of a metal atom and R1, R2, R3, R4, RS, RB, R7, R8a, R8b, R9, R10 and n (unless otherwise defined) have the meanings given above.
Bei den vorstehend aufgeführten Umsetzungen können die Verbindungen II-XIV eis solche oder gegebenenfalls in Form ihrer Salze eingesetzt werden.In the reactions listed above, the compounds II-XIV may be used in such or, if appropriate, in the form of their salts.
Weitere erfindungsgemäße Verfahrensaspekte bestehen darin, daß man Verbindungen I aus Ausgangsverbindungen II bis XII herstellt, in denen R1, R2, R3, R4, R5, R6, R7 , R8a, R8b, R9, R10 und n wie vorstehend angegeben nSher definiert sind.Further aspects of the process according to the invention are that compounds I are prepared from starting compounds II to XII in which R1, R2, R3, R4, R5, R6, R7, R8a, R8b, R9, R10 and n are defined as specified above.
Die Herstellungsverfahren a), b) und c) führen zu den erfindungsgemäßen Sulfiden, die Oxidation der Verbindungen VIII und die Verfahren d) und e) liefern die erfindungsgemäßen Sulfoxide, die Verfahren f), g) und h) führen zu beiden Produktklassen.The production processes a), b) and c) lead to the sulfides according to the invention, the oxidation of the compounds VIII and processes d) and e) give the sulfoxides according to the invention, the processes f), g) and h) lead to both product classes.
Welche Abgangsgruppen Y, Y', Y", Z, Z' bzw. Z " geeignet sind, ist dem Fachmann aufgrund seines Fachwissens geläufig. Eine geeignete Abgangsgruppe Y ist beispielsweise eine Gruppe, die zusammen mit der Sulfinylgruppe, an die sie gebunden ist, ein reaktives Sulfinsäurederivat bildet. Als geeignete Abgangsgruppe Y seien beispielsweise Alkoxy-, Dialkylamino-oder Alkylmercaptogruppen genannt. Eine geeignete Abgangsbzw. Reaktivgruppe Y' ist eine Gruppe, die mit einer sekundären Aminogruppe unter Abspaltung von HY' oder unter Anlagerung zu reagieren in der Lage ist. Bei Verbindungen der Formel XIII, in denen R5' insbesondere eine substituierte Carbonylgruppe darstellt, ist Y' beispielsweise eine Abgangsgruppe, die zusammen mit der Carbonylgruppe, an die sie gebunden ist, ein reaktives Carbonsäurederivat, z.B. ein Säurehalogenid, bildet. ErfindungsgemäB sind durch die allgemeine Formel R5'-Y' (XIII) auch solche Verbindungen (Vorläufer der unter physiologischen Bedingungen leicht abspaltbaren Gruppe R5) umfaßt, bei denen Y' eine Reaktivgruppe darstellt (z.B. Isonitrile), die bei der Reaktion mit der sekundären Aminogruppe keine Kondensation unter Abspaltung von HY' sondern eine Addition unter Bildung der gewünschten abspaltbaren Gruppe R5 durchlaufen.The person skilled in the art is familiar with which leaving groups Y, Y ', Y ", Z, Z' and Z" are suitable, on the basis of his specialist knowledge. A suitable leaving group Y is, for example, a group which, together with the sulfinyl group to which it is attached, forms a reactive sulfinic acid derivative. Examples of suitable leaving groups Y are alkoxy, dialkylamino or alkyl mercapto groups. A suitable outlet or Reactive group Y 'is a group which is able to react with a secondary amino group with elimination of HY' or with addition. For compounds of formula XIII, in which R5 'represents in particular a substituted carbonyl group, Y' is for example a leaving group which together with the carbonyl group to which it is attached is a reactive carboxylic acid derivative, e.g. an acid halide. According to the invention, the general formula R5'-Y '(XIII) also encompasses those compounds (precursors of the group R5 which can easily be split off under physiological conditions) in which Y' represents a reactive group (for example isonitriles) which are involved in the reaction with the secondary amino group no condensation with elimination of HY 'but an addition to form the desired cleavable group R5.
Die Abgangsgruppe Y'' ist eine dem Fachmann für Alkylierungsreaktinnen geläufige Gruppe, die bei der Alkylierung - z.B. mit Dialkylsulfat, Fluorsulfonsäurealkylester oder Alkyliodld - abgeht.The leaving group Y ″ is one of ordinary skill in the art for alkylation reactions common group that goes off during the alkylation - for example with dialkyl sulfate, alkyl fluorosulfonate or alkyl iodide.
Als geeignete Abgangsgruppen Z, Z' bzw. Z" seien beispielsweise Halogenatome, insbesondere Chloratome, oder durch Veresterung (z.B. mit p-Toluolsulfonsäure) aktivierte Hydroxylgruppen genannt.Suitable leaving groups Z, Z 'or Z "are, for example, halogen atoms, in particular chlorine atoms, or hydroxyl groups activated by esterification (e.g. with p-toluenesulfonic acid).
Das Xquivalent eines Metallatoms M' ist beispielsweise ein Alkalimetall (Li, Na oder K), oder ein Erdalkalimetallatom (z.B. Mg), das durch ein Halogenatom (z.B. Br, Grignard-Reagenz) substituiert ist, oder irgendein anderes, gegebenenfalls substituiertes Metallatom, von dem bekannt ist, daß es bei Substitutionsreaktionen metallorganischer Verbindungen wie die obenerwähnten Metalle reagiert.The X equivalent of a metal atom M 'is, for example, an alkali metal (Li, Na or K), or an alkaline earth metal atom (eg Mg), which is substituted by a halogen atom (eg Br, Grignard reagent), or any other optionally substituted metal atom which is known to react in the substitution reactions of organometallic compounds such as the metals mentioned above.
Die Umsetzung von II mit III erfolgt in an sich bekannter Weise in geeigneten, vorzugsweise polaren protischen oder aprotischen Lösungsmitteln (wie Methanol, Isopropanol, Dimethylsulfoxid, Aceton, Dimethyl- formamid oder Acetonitril) unter Zusatz oder unter Ausschluß von Wasser. Sie wird beispielsweise in Gegenwart eines Protonenakzeptors durchgeführt. Als solche eignen sich Alkalimetallhydroxide, wie Natriumhydroxid, Alkalimetallcarbonate, wie Kaliumcarbonat, oder tertiäre Amine, wie Pyridin, Trlethylamin oder Ethyldiisopropylamin. Alternativ kann die Umsetzung auch ohne Protonenakzeptor durchgeführt werden, wobei - je nach Art der Ausgangsverbindungen - gegebenenfalls zunächst die Säureadditionssalze in besonders reiner Form abgetrennt werden können. Die Reaktionstemperatur kann zwischen 0° und 150°C liegen, wobei in Gegenwart von Protonenakzeptoren Temperaturen zwischen 20° und 80°C und ohne Protonenakzeptoren zwischen 60° und 120°C - insbesondere die Siedetemperatur der verwendeten Lösungsmittel - bevorzugt sind. Die Reaktionszeiten liegen zwischen 0,5 und 12 Stunden.The reaction of II with III is carried out in a manner known per se in suitable, preferably polar protic or aprotic solvents (such as methanol, isopropanol, dimethyl sulfoxide, acetone, dimethylformamide or acetonitrile) with or without water. It is carried out, for example, in the presence of a proton acceptor. Alkali metal hydroxides such as sodium hydroxide, alkali metal carbonates such as potassium carbonate or tertiary amines such as pyridine, trlethylamine or ethyldiisopropylamine are suitable as such. Alternatively, the reaction can also be carried out without a proton acceptor, with the acid addition salts optionally being able to be separated off in a particularly pure form, depending on the nature of the starting compounds. The reaction temperature can be between 0 ° and 150 ° C, in the presence of proton acceptors temperatures between 20 ° and 80 ° C and without proton acceptors between 60 ° and 120 ° C - especially the boiling point of the solvents used - are preferred. The response times are between 0.5 and 12 hours.
Bei der Umsetzung von IV mit V, die in an sich bekannter Weise erfolgt, kommen ähnliche Reaktionsbedingungen wie bei der Umsetzung von II mit III zur Anwendung.In the reaction of IV with V, which is carried out in a manner known per se, similar reaction conditions are used as in the reaction of II with III.
Die Reaktion von VI mit VII wird bevorzugt in polaren, gegebenenfalls wasserhaltigen Lösungsmitteln in Gegenwart einer starken Säure, z.B. Salzsäure, insbesondere bei der Siedetemperatur des verwendeten Lösungsmittels durchgeführt.The reaction of VI with VII is preferred in polar, optionally water-containing solvents in the presence of a strong acid, for example hydrochloric acid, in particular at the boiling point of the used Solvent carried out.
Die Oxidation der Sulfide VIII erfolgt in an sich bekannter Weise und unter den Bedingungen, wie sie dem Fachmann für die Oxidation von Sulfiden zu Sulfoxiden geläufig sind {siehe hierzu z.B. J. Drabowicz und M. Mikolajczyk, Organic preparations and procedures int. 14(1-2). 45-89(1982) oder E. Block in S. Patal, The Chemistry of Functlonal Groups, Supplement E. Part 1, S. 539-608, John Wiley and Sons (Intersclence Publicatlon), 1980}. Als Oxidationsmittel kommen alle für die Oxidation von Sulfiden zu Sulfoxiden üblicherweise verwendeten Reagenzien in Frage, insbesondere Peroxysiuren, wie z.B. Peroxyessigsäure, Trifluorperoxyessigsäure, 3,5-Dinitroperoxybenzoesäure, Peroxymaleinsäure oder bevorzugt m-Chlorperoxybenzoesäure.The oxidation of sulfides VIII takes place in a manner known per se and under the conditions known to the person skilled in the art for the oxidation of sulfides to sulfoxides {see, for example, J. Drabowicz and M. Mikolajczyk, Organic preparations and procedures int. 14 (1-2). 45-89 (1982) or E. Block in S. Patal, The Chemistry of Functlonal Groups, Supplement E. Part 1, pp. 539-608, John Wiley and Sons (Intersclence Publicatlon), 1980}. Suitable oxidizing agents are all reagents commonly used for the oxidation of sulfides to sulfoxides, in particular peroxy acids, e.g. Peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoic acid, peroxymaleic acid or preferably m-chloroperoxybenzoic acid.
Die Reaktionszeit liegt (je nach Reaktivität des Oxidationsmittels und Verdünnungsgrad zwischen -70°C und der Siedetemperatur des verwendeten Lösungsmittels, bevorzugt jedoch zwischen -30°C und +20°C. Als vorteilhaft hat sich auch die Oxidation mit Halogenen bzw. mit Hypohalogeniten (z.B. mit wäßriger Natriumhypochloritlösung) erwiesen, die zweckmä8igerweise bei Temperaturen zwischen 0° und 30°C durchgeführt wird. Die Reaktion wird zweckmäßigerweise in inerten Lösungsmitteln, z.B. aromatischen oder chlorierten Kohlenwasserstoffen, wie Benzol, Toluol, Dichlormethan oder Chloroform, vorzugsweise in Estern oder Ethern, wie Essigsäureethylester, Essigsäureisopropylester oder Dloxan durchgeführt.The reaction time is (depending on the reactivity of the oxidizing agent and degree of dilution between -70 ° C and the boiling point of the solvent used, but preferably between -30 ° C and + 20 ° C. Oxidation with halogens or with hypohalites has also been found to be advantageous ( eg with aqueous sodium hypochlorite solution), which is expediently carried out at temperatures between 0 ° and 30 ° C. The reaction is advantageously carried out in inert solvents, for example aromatic or chlorinated hydrocarbons, such as benzene, toluene, dichloromethane or chloroform, preferably in esters or ethers, such as ethyl acetate, isopropyl acetate or dloxane.
Die Umsetzung von IX mit X erfolgt bevorzugt in inerten Lösungsmitteln, wie sie auch für die Reaktion von Enolationen mit Alkylierungsmitteln üblicherweise verwendet werden. Beispielsweise seien aromatische Lösungsmittel wie 8enzol oder Toluol genannt. Die Reaktionstemperatur liegt (je nach Art des Alkalimetallatoms M und der Abgangsgruppe Z) in der Regel zwischen 0° und 120°C, wobei die Siedetemperatur des verwendeten Lösungsmittels bevorzugt ist. Beispielsweise [wenn M Li(Lithium) und Z Cl (Chlor) darstellt und die Umsetzung in Benzol durchgeführt wird] ist die Siedetemperatur von Benzol (80°C) bevorzugt.The reaction of IX with X is preferably carried out in inert solvents, as are usually used for the reaction of enolate ions with alkylating agents. For example, aromatic solvents such as 8enzene or toluene may be mentioned. The reaction temperature is (depending on the nature of the alkali metal atom M and the leaving group Z) generally between 0 ° and 120 ° C, with the boiling point of the solvent used being preferred. For example [when M represents Li (lithium) and Z Cl (chlorine) and the reaction is carried out in benzene], the boiling point of benzene (80 ° C.) is preferred.
Die Verbindungen XI werden mit den Verbindungen XI I in an sich bekannter Weise umgesetzt, wie sie dem Fachmann für die Reaktion metallorga nischer Verbindungen geläufig ist.The compounds XI are reacted with the compounds XI I in a manner known per se, as is known to the person skilled in the art for the reaction organorga African connections is common.
Die Umsetzung gemäB Verfahrensvariante f) erfolgt in dem Fachmann bekannter Weise in geeigneten Lösungsmitteln wie Tetrahydrofüran oder Acetonltril, gegebenenfalls unter Zusatz einer Base (falls Y' eine Abgangsgruppe darstellt) oder auch ohne Basenzusatz (falls Y' eine Reaktivgruppe darstellt). Bei unsymmetrischer Verteilung der Substituenten R1, R2, R3 und R4 liefert diese Reaktion Isomerengemische, die durch geeignete Trennverfahren (z.B. Chromatographie) aufgetrennt werden müssen.The reaction according to process variant f) is carried out in a manner known to those skilled in the art in suitable solvents such as tetrahydrofuran or acetone tril, optionally with the addition of a base (if Y 'represents a leaving group) or without addition of base (if Y' represents a reactive group). With asymmetrical distribution of the substituents R1, R2, R3 and R4, this reaction gives mixtures of isomers which have to be separated by suitable separation processes (e.g. chromatography).
Die Solvolyse gemäß Verfahrensvariante g) erfolgt in dem Fachmann bekannter Weise in geeigneten, Wasser enthaltenden oder Wasser abspaltenden alkalischen oder sauren Lösungen, bei Raumtemperatur oder gewünschtenfalls unter Erwärmen bis zur Siedetemperatur des eingesetzten Lösungsmittels.Solvolysis according to process variant g) is carried out in a manner known to those skilled in the art in suitable water-containing or water-splitting alkaline or acidic solutions, at room temperature or, if desired, with heating to the boiling point of the solvent used.
Die Alkylierung gemäß Verfahrensvariante h) erfolgt - gegebenenfalls nach vorheriger Oeprotonierung - in dem Fachmann geläufiger Weise in geeigneten inerten Lösungsmitteln.The alkylation according to process variant h) is carried out - if appropriate after prior protonation - in a manner familiar to those skilled in the art in suitable inert solvents.
Je nach Art der Ausgangsverbindungen, die gegebenenfalls auch in Form ihrer Salze eingesetzt werden können, und in Abhängigkeit von den Reaktionsbedingungen werden die erfindungsgemäßen Verbindungen zunächst entweder als solche oder in Form ihrer Salze gewonnen.Depending on the nature of the starting compounds, which can optionally also be used in the form of their salts, and depending on the reaction conditions, the compounds according to the invention are initially obtained either as such or in the form of their salts.
Im übrigen erhält man die Salze durch Auflösen der freien Verbindungen in einem geeigneten Lösungsmittel, z.B. in einem chlorierten Kohlenwasserstoff, wie Methylenchlorid oder Chloroform, einem niedermolekularen aliphatischen Alkohol (Ethanol, Isopropanol), einem EtherOtherwise, the salts are obtained by dissolving the free compounds in a suitable solvent, e.g. in a chlorinated hydrocarbon such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol (ethanol, isopropanol), an ether
(Diisopropylether), einem Keton (Aceton) oder Wasser, das die gewünschte Säure bzw. Base enthält, oder dem die gewünschte Säure bzw. Base - gegebenenfalls in der genau berechneten stöchiometrischen Menge anschließend zugegeben wird.(Diisopropyl ether), a ketone (acetone) or water, which contains the desired acid or base, or to which the desired acid or base is added, if appropriate in the precisely calculated stoichiometric amount.
Die Salze werden durch Filtrieren, Umfallen, Ausfällen oder durch Verdampfen des Lösungsmittels gewonnen. Erhaltene Salze können durch Alkalisieren bzw. Ansäuern, z.B. mit wäßrigem Natriumhydrogencarbonat bzw. mit verdünnter Salzsäure, in die freien Verbindungen umgewandelt werden, welche wiederum in die Salze übergeführt werden können. Auf diese Weise lassen sich die Verbindungen reinigen, oder es lassen sich pharmakologisch nicht verträgliche Salze in pharmakologisch verträgliche Salze umwandeln.The salts are obtained by filtration, reprecipitation, precipitation or by evaporation of the solvent. Salts obtained can be converted into the free compounds by alkalization or acidification, for example with aqueous sodium hydrogen carbonate or with dilute hydrochloric acid, which in turn can be converted into the salts. In this way, the compounds can be purified or pharmacologically unacceptable salts can be converted into pharmacologically acceptable salts.
Die erfindungsgemäßen Sulfoxide sind optisch aktive Verbindungen. Je nach Art der Substituenten R1 bis R10 können noch weitere ChiralitätsZentren im Molekül sein (z.B. wenn R6 kein Wasserstoff ist). Oie Erfindung umfaßt daher sowohl die Enantiomeren und Diastereomeren als auch ihre Mischungen und Racemate. Die Enantiomeren können in an sich bekannter Weise (beispielsweise durch Herstellung und Trennung entsprechender diastereoisomerer Verbindungen) separiert werden. Die Enantiomeren können aber auch durch asymmetrische Synthese, beispielsweise durch Reaktion optisch aktiver reiner Verbindungen XI oder diastereoisomer reiner Verbindungen XI mit Verbindungen XII hergestellt werden [siehe hierzu K.K. Andersen, Tetrahedron Lett., 93 (1962)].The sulfoxides according to the invention are optically active compounds. Depending on the nature of the substituents R1 to R10, there may be additional chiral centers in the molecule (e.g. if R6 is not hydrogen). The invention therefore encompasses both the enantiomers and diastereomers as well as their mixtures and racemates. The enantiomers can be separated in a manner known per se (for example by preparing and separating corresponding diastereoisomeric compounds). However, the enantiomers can also be prepared by asymmetric synthesis, for example by reaction of optically active pure compounds XI or diastereoisomerically pure compounds XI with compounds XII [see K.K. Andersen, Tetrahedron Lett., 93 (1962)].
Die erfindungsgemäβen Verbindungen werden bevorzugt durch Umsetzung von II mit III und gegebenenfalls anschließende Oxidation des entstandenen Sulfids VIII synthetisiert.The compounds according to the invention are preferably synthesized by reacting II with III and, if appropriate, subsequent oxidation of the sulfide VIII formed.
Die Verbindungen II, IV, VI, IX, XI, XIII und XIV sind entweder bekannt, oder sie können nach bekannten Vorschriften ausgehend von bekannten oder in bekannter Weise erhältlichen Vorprodukten in analoger Weise erhalten werden [siehe z.B. DE-OS 28 48 531; J. Org. Chem. 44 , 2907-2910 (1979); J. Org. Chem. 29, 1-11 (1964); DE-OS 20 29 556; J. Fluorine Chem. 18, 281-91 (1981); Synthesis 1980, 727-8].The compounds II, IV, VI, IX, XI, XIII and XIV are either known, or they can be obtained analogously according to known regulations, starting from known or obtainable precursors [see e.g. DE-OS 28 48 531; J. Org. Chem. 44, 2907-2910 (1979); J. Org. Chem. 29, 1-11 (1964); DE-OS 20 29 556; J. Fluorine Chem. 18: 281-91 (1981); Synthesis 1980, 727-8].
Die Verbindungen III sind neu und ebenfalls Gegenstand der Erfindung. Sie sind aus entsprechenden, in 4-Position unsubstituierten Pyridinen durch N-Oxidation (z.B. mit Wasserstoffperoxid), Nitrierung in 4-Position (z.B. mit rauchender Salpetersäure), Austausch der Nitrogruppe gegen ein Chloratom (z.B. mit konzentrierter Salzsäure), Umsetzung mit einem Amin HN(R8a)R8b und entsprechende weitere Umsetzungen, wie in der EP-A-0 103 553 oder EP-A-0 080 602 beschrieben, in für den Fachmann bekannter Weise erhältlich. Die Verbindungen V, VII und XII sind z. B. aus den Verbindungen III in dem Fachmann bekannter Welse zugSnglich. Verbindungen X werden in Anlehnung an Z. Talik, Roczniki Chem. 35, 475 (1961) hergestellt.The compounds III are new and also a subject of the invention. They are made from corresponding pyridines unsubstituted in the 4-position by N-oxidation (e.g. with hydrogen peroxide), nitration in the 4-position (e.g. with fuming nitric acid), exchange of the nitro group for a chlorine atom (e.g. with concentrated hydrochloric acid), reaction with an amine HN (R8a) R8b and corresponding further reactions, as described in EP-A-0 103 553 or EP-A-0 080 602, can be obtained in a manner known to those skilled in the art. The compounds V, VII and XII are e.g. B. from the compounds III in catfish known to those skilled in the art. Compounds X are prepared based on Z. Talik, Roczniki Chem. 35, 475 (1961).
Die folgenden Beispiele erlSutern die Erfindung näher ohne sie einzuschränken. Die in den Beispielen namentlich aufgeführten Verbindungen der allgemeinen Formel I sowie die Salze dieser Verbindungen sind be vorzugter Gegenstand der Erfindung. Schmp. bedeutet Schmelzpunkt, für Stunde(n) wird die Abkürzung h und für Minuten die Abkürzung Min. verwendet. Unter "Ether" wird Diethylether verstanden. Die Η-NMR-Spektren wurden mit einem 60 MHz-Gerät aufgenommen (interner Standard: Tetramethylsilan). The following examples illustrate the invention without restricting it. The compounds of general formula I mentioned by name in the examples and the salts of these compounds are the preferred subject of the invention. Mp means melting point, the abbreviation h is used for hour (s) and the abbreviation min is used for minutes. "Ether" means diethyl ether. The Η NMR spectra were recorded with a 60 MHz device (internal standard: tetramethylsilane).
BeispieleExamples
EndprodukteEnd products
1. 6-[4-Dimethylaminopvridyl-(2)-methylsulfinvl]-2.2-difluor- 5H-[1.31-dioxolo[4.5-f]benzimidazol1. 6- [4-Dimethylaminopvridyl- (2) -methylsulfinvl] -2.2-difluoro-5H- [1.31-dioxolo [4.5-f] benzimidazole
Zu einer Suspension von 1,5 g (4,12 mmol) 6-[4-Dimethylaminopyridyl- (2)-methylthio]-2,2-difluor-5H-[1,3]-dioxolo[4,5-f]benzimidazol in 7,5 ml Dichlormethan tropft man bei -30°C während 0,5 h eine Lösung von 1,35 g (6,9 mmol) 80%ige m-Chlorperoxybenzoesäure in 7,5 ml Dichlor- methan und rührt die Mischung unter dünnschichtchromatographlscher Kontrolle bis das Thlo-Derivat vollständlg umgesetzt ist. Danach gibt man das Reaktionsgemisch auf 15 ml konzentrierte Ammoniaklösung und extrahiert dreimal mit je 15 ml Dichlormethan. Die organische Phase wird getrocknet und im Rotationsverdampfer bei Raumtemperatur eingeengt. Der Rückstand wird mit wenig Dichlormethan nachgewaschen. Ausbeute: 0,8 g (52% der Theorie) gelbliches Pulver. Schmp.: 173-177°C (Zersetzung). 1H-NMR (DMSO-d6): 2,86 ppm (s, 6H); 4,56 ppm (verbreitertes s, ca. 2 H); 6,42-6,64 ppm (m, 2H); 7,62 ppm (s, 2H); 8,1 ppm (d, 1H).To a suspension of 1.5 g (4.12 mmol) of 6- [4-dimethylaminopyridyl- (2) -methylthio] -2,2-difluoro-5H- [1,3] -dioxolo [4,5-f] benzimidazole in 7.5 ml dichloromethane is added dropwise at -30 ° C. for 0.5 h, a solution of 1.35 g (6.9 mmol) 80% m-chloroperoxybenzoic acid in 7.5 ml dichloromethane and the mixture is stirred under thin-layer chromatography until the Thlo derivative has been completely converted. The reaction mixture is then poured into 15 ml of concentrated ammonia solution and extracted three times with 15 ml of dichloromethane each time. The organic phase is dried and concentrated in a rotary evaporator at room temperature. The residue is washed with a little dichloromethane. Yield: 0.8 g (52% of theory) of yellowish powder. Mp: 173-177 ° C (decomposition). 1H NMR (DMSO-d 6 ): 2.86 ppm (s, 6H); 4.56 ppm (broadened s, approx. 2 H); 6.42-6.64 ppm (m, 2H); 7.62 ppm (s, 2H); 8.1 ppm (d, 1H).
Analog erhält man ausAnalogously you get from
2-[ 4-Dimethylamino-pyridyl-(2)-methylthio]-5-trifluormethoxy-1H-benz- imidazol,2- [4-dimethylamino-pyridyl- (2) -methylthio] -5-trifluoromethoxy-1H-benzimidazole,
5-Difluormethoxy-2-[4-dimethylamino-pyridyl-(2)-methylthio]-6-methoxy-5-difluoromethoxy-2- [4-dimethylamino-pyridyl- (2) -methylthio] -6-methoxy-
1H-benzimidazol, 5-Difluormethoxy-2-[4-dimethylamino-pyridyl-(2)-methylthio]-1H-benzimidazol,1H-benzimidazole, 5-difluoromethoxy-2- [4-dimethylamino-pyridyl- (2) -methylthio] -1H-benzimidazole,
2-[4-Dimethylamino-pyridyl-(2)-methylthio]-5-(1,1,2,2-tetrafluor- ethoxy)-1H-benzimidazol,2- [4-dimethylamino-pyridyl- (2) -methylthio] -5- (1,1,2,2-tetrafluoroethoxy) -1H-benzimidazole,
2-[4-Dimethylamino-pyridyl-(2)-methylthio]-6,6,7-trifluor-6,7-dihydro- 1H-(1,4]-dioxino[2,3-f]benzimidazol,2- [4-dimethylamino-pyridyl- (2) -methylthio] -6,6,7-trifluoro-6,7-dihydro-1H- (1,4] -dioxino [2,3-f] benzimidazole,
2-[4-Dimethylamino-6-methyl-pyridyl-(2)-methylthio]-5-trifluormethoxy-2- [4-dimethylamino-6-methyl-pyridyl- (2) -methylthio] -5-trifluoromethoxy-
1H-benzimidazol,1H-benzimidazole,
5-Difluormethoxy-2-[4-dimethylamino-6-methyl-pyridyl-(2)-methylthio]-6- (aethoxy-1H-benzimidazol,5-difluoromethoxy-2- [4-dimethylamino-6-methyl-pyridyl- (2) -methylthio] -6- (ethoxy-1H-benzimidazole,
5-Difluormethoxy-2-[4-dimethylamino-6-methyl-pyridyl- ( 2 ) -methylthio]-5-difluoromethoxy-2- [4-dimethylamino-6-methyl-pyridyl- (2) -methylthio] -
1H-benzimidazol,1H-benzimidazole,
2 , 2-Difluor-6-[4-methylamlno-pyrldyl- (2 ) -methylthio]-5H-[ 1 , 3]-dioxolo- [4 , 5-flbenzimidazol,2,2-difluoro-6- [4-methylamlno-pyrldyl- (2) -methylthio] -5H- [1,3] -dioxolo- [4,5-flbenzimidazole,
2 , 2-Dif luor-6-[4-morpholino-pyridyl- ( 2 ) -methylthio]-5H-[ 1 , 3]-dioxolo-2,2-difluoro-6- [4-morpholino-pyridyl- (2) -methylthio] -5H- [1,3] -dioxolo-
( 4 , 5-f ]benzimidazol,(4,5-f] benzimidazole,
6-[4-Dimethylamino-6-methyl-pyridyl- ( 2 ) -methylthio]-2 , 2-difluor-5H-6- [4-dimethylamino-6-methyl-pyridyl- (2) -methylthio] -2, 2-difluoro-5H-
[1, 3]-dioxolo[4,5-f]benzimidazol, 6-[4-Acetylamino-pyridyl-(2)-methylthio]-2,2-difluor-5H-[1,3]-dioxolo-[1, 3] -dioxolo [4,5-f] benzimidazole, 6- [4-acetylamino-pyridyl- (2) -methylthio] -2,2-difluoro-5H- [1,3] -dioxolo-
[4,5-f]benzimidazol,[4,5-f] benzimidazole,
2-[4-Methylamino-pyridyl-(2)-methylthio]-5-(1,1,2,2-tetrafluorethoxy)-2- [4-methylamino-pyridyl- (2) -methylthio] -5- (1,1,2,2-tetrafluoroethoxy) -
1H-benzimidazol,1H-benzimidazole,
6,6,7-Trifluor-2-[4-methylamlno-pyridyl-(2)-methylthio]-6,7-dihydro-1H- [1,4]-dioxino[2,3-f]benzimidazol,6,6,7-trifluoro-2- [4-methylamlno-pyridyl- (2) -methylthio] -6,7-dihydro-1H- [1,4] -dioxino [2,3-f] benzimidazole,
2-[4-Morpholino-pyridyl-(2)-methylthio]-5-trifluormethoxy-1H-benzimida- zol und2- [4-Morpholino-pyridyl- (2) -methylthio] -5-trifluoromethoxy-1H-benzimidazole and
5-Difluormethoxy-6-methoxy-2-[4-morpholino-pyridyl-(2)-methylthio]-1H- benzimidazol5-difluoromethoxy-6-methoxy-2- [4-morpholino-pyridyl- (2) -methylthio] -1H-benzimidazole
durch Oxidation mit m-Chlorperoxybenzoesäureby oxidation with m-chloroperoxybenzoic acid
2-[4-Dimethylamino-pyridyl-(2)-methylsulfinyl]-5-trifluormethoxy-1H- benzimidazol,2- [4-dimethylamino-pyridyl- (2) -methylsulfinyl] -5-trifluoromethoxy-1H-benzimidazole,
5-Difluormethoxy-2-[4-dimethylamino-pyridyl-(2)-methylsulfinyl]-6- methoxy-1H-benzimidazol,5-difluoromethoxy-2- [4-dimethylamino-pyridyl- (2) -methylsulfinyl] -6-methoxy-1H-benzimidazole,
5-Difluormethoxy-2-[4-dimethylamino-pyridyl-(2)-methylsulfinyl]-1H- benzimidazol,5-difluoromethoxy-2- [4-dimethylamino-pyridyl- (2) -methylsulfinyl] -1H-benzimidazole,
2-[4-Dimethylamino-pyridyl-(2)-methylsulfinyl]-5-(1,1,2,2-tetrafluor- ethoxy]-1H-benzimidazol, 2-[4-Dimethylamino-pyridyl-(2)-methylsulfinyl]-6,6,7-trifluor-6,7-di- hydro-1H-[1,4]-dioxlno[2,3-f]benzimidazol,2- [4-Dimethylamino-pyridyl- (2) -methylsulfinyl] -5- (1,1,2,2-tetrafluoro-ethoxy] -1H-benzimidazole, 2- [4-dimethylamino-pyridyl- (2) -methylsulfinyl ] -6,6,7-trifluoro-6,7-di-hydro-1H- [1,4] dioxlno [2,3-f] benzimidazole,
2-[4-Dimethylamino-6-methyl-pyridyl-(2)-methylsulfinyl]-5-trifluormethoxy-1H-benzimidazol,2- [4-dimethylamino-6-methyl-pyridyl- (2) -methylsulfinyl] -5-trifluoromethoxy-1H-benzimidazole,
5-Difluormethoxy-2-[4-dimethylamino-6-methyl-pyridyl-(2)-methyl- sulfinyl]-6-methoxy-1H-benzimidazol,5-difluoromethoxy-2- [4-dimethylamino-6-methyl-pyridyl- (2) -methylsulfinyl] -6-methoxy-1H-benzimidazole,
5-Difluormethoxy-2-[4-dimethylamino-6-methyl-pyridyl-(2)-methylsulfinyl]-1H-benzimidazol,5-difluoromethoxy-2- [4-dimethylamino-6-methyl-pyridyl- (2) -methylsulfinyl] -1H-benzimidazole,
2,2-Difluor-6-[4-methylamino-pyridyl-(2)-methylsulfinyl]-5H-[1,3]- dioxolo[4,5-f]benzimidazol,2,2-difluoro-6- [4-methylamino-pyridyl- (2) -methylsulfinyl] -5H- [1,3] - dioxolo [4,5-f] benzimidazole,
2,2-Difluor-6-[4-morphollno-pyridyl-(2)-methylsulfinyl]-5H-[1,3]- dioxolo[4,5-f]benzimidazol,2,2-difluoro-6- [4-morphollno-pyridyl- (2) -methylsulfinyl] -5H- [1,3] - dioxolo [4,5-f] benzimidazole,
6-[4-Dimethylamino-6-methyl-pyridyl-(2)-methylsulfinyl]-2,2-difluor-5H- [1,3]-dioxolo[4,5-f]benzimidazol,6- [4-dimethylamino-6-methyl-pyridyl- (2) -methylsulfinyl] -2,2-difluoro-5H- [1,3] -dioxolo [4,5-f] benzimidazole,
6-[4-Acetylamino-pyridyl-(2)-methylsulfinyl]-2,2-difluor-5H-[1,3]- dioxolo[4,5-f]benzimidazol,6- [4-acetylamino-pyridyl- (2) -methylsulfinyl] -2,2-difluoro-5H- [1,3] - dioxolo [4,5-f] benzimidazole,
2-[4-Methylamino-pyridyl-(2)-methylsulfinyl]-5-(1,1,2,2-tetrafluor- ethoxy)-1H-benzimidazol, 6,6,7-Trifluor-2-[4-methylamino-pyridyl-(2)-methylsulfinyl]-6,7-di- hydro-1H-[1,4]-dioxino[2,3-f]benzimidazol,2- [4-Methylamino-pyridyl- (2) -methylsulfinyl] -5- (1,1,2,2-tetrafluoroethoxy) -1H-benzimidazole, 6,6,7-trifluoro-2- [4-methylamino -pyridyl- (2) -methylsulfinyl] -6,7-di-hydro-1H- [1,4] -dioxino [2,3-f] benzimidazole,
2-[4-Morpholino-pyridyl-(2)-methylsulfinyl]-5-trifluormethoxy-1H-benz- imidazol und2- [4-Morpholino-pyridyl- (2) -methylsulfinyl] -5-trifluoromethoxy-1H-benzimidazole and
5-Difluormethoxy-6-methoxy-2-[4-morphollno-pyridyl-(2)-methylsulfinyl]- IH-benzimidazol.5-difluoromethoxy-6-methoxy-2- [4-morphollno-pyridyl- (2) -methylsulfinyl] - IH-benzimidazole.
2. 6-[4-Dlmethylamino-3-methyl-Dyridyl-(2)-methylsulfinyl]-2.2- difluor-5H-[1.3]-dioxolo[4.5-fIbenzimidazol2. 6- [4-dimethylamino-3-methyldyridyl- (2) -methylsulfinyl] -2.2-difluoro-5H- [1.3] -dioxolo [4.5-f-benzimidazole
Entsprechend Beispiel 1 erhält man aus 5,6 g (15 mmol) 6-[4-Dimethyl- amino-3-methylpyridyl-(2)-methylthiol-2,2-difluor-5H-[ 1.3]-dioxolo- [4, 5-f ]benzimidazol nach chromatographischer Reinigung an Kieselgel (Fließmittel Ethylacetat/Ethanol/konz. Ammoniak 20:4:1) und Ausrühren mit Dichlormethan/Diethylether 1,2 g (20% der Theorie) der Titelverbindung vom Schmp. 170-171°C (Zersetzung).According to Example 1, 5.6 g (15 mmol) of 6- [4-dimethylamino-3-methylpyridyl- (2) -methylthiol-2,2-difluoro-5H- [1.3] -dioxolo- [4, 5-f] benzimidazole after chromatographic purification on silica gel (eluent ethyl acetate / ethanol / concentrated ammonia 20: 4: 1) and stirring with dichloromethane / diethyl ether 1.2 g (20% of theory) of the title compound of mp 170-171 ° C (decomposition).
3. 5-Difluormethoxy-2-[3-methyl-4-moroholinopyridyl-(2)-methyl- sulfinyl]-1H-benzimidazol3. 5-Difluoromethoxy-2- [3-methyl-4-moroholinopyridyl- (2) -methylsulfinyl] -1H-benzimidazole
Entsprechend Beispiel 1 erhält man aus 3,1 g (7,63 mmol) 5-Difluor- methoxy-2-[3-methyl-4-morpholinopyridyl-(2)-methylthio]-1H-benzimidazol nach Ausrühren mit Dichlormethan 1 g (30% der Theorie) der Titelverbindung vom Schmp. 149-150°C (Zersetzung).According to Example 1, 3.1 g (7.63 mmol) of 5-difluoromethoxy-2- [3-methyl-4-morpholinopyridyl- (2) -methylthio] -1H-benzimidazole are obtained after stirring with dichloromethane to 1 g ( 30% of theory) of the title compound of mp. 149-150 ° C (decomposition).
4. 2.2-Difluor-6-[3-methyl-4-moroholinooyridyl-(2)-methylsulfinyl]- 5H-[1.3]-dioxolo[4,5-fIbenzimidazol Entsprechend Beispiel 1 erhält man aus 3,7 g (8,8 mmol) 2,2-Difluor-6- [3-methyl-4-morpholinopyridyl-(2)-methylthio]-5H-[1,3]-dioxolo[4,5-f]- benzimidazol nach Ausrühren mit Dichlormethan und Methanol 2,5 g (65% der Theorie) der Titelverbindung vom Schmp. 132-194°C (Zersetzung).4. 2,2-difluoro-6- [3-methyl-4-moroholinooyridyl- (2) -methylsulfinyl] - 5H- [1.3] -dioxolo [4,5-f-benzimidazole According to Example 1, 3.7 g (8.8 mmol) of 2,2-difluoro-6- [3-methyl-4-morpholinopyridyl- (2) -methylthio] -5H- [1,3] -dioxolo [ 4,5-f] - benzimidazole after stirring with dichloromethane and methanol 2.5 g (65% of theory) of the title compound of mp. 132-194 ° C (decomposition).
5. 2 , 2-Difluor-6- [ 3methy1-4-pyrrolidinyl-(1)-pyridyl-(21-methylsul- finyl]-5H-[1.3l-dioxolo[4.5-fIbenzimidazol5. 2, 2-Difluoro-6- [3methy1-4-pyrrolidinyl- (1) pyridyl- (21-methylsulfinyl) -5H- [1.3l-dioxolo [4.5-fbenzimidazole
Entsprechend Beispiel 1 erhält man aus 1 g (2,5 mmol) 2,2-Difluor-6-[3- methyl-4-pyrrolidinyl-(1)-pyridyl-(2)-methylthio]-5H-[1,3]-dioxolo- [4,5-f]benzimidazol nach Chromatographie an Kieselgel (Fließmittel: Ethylacetat/ Ethanol/konz. Ammoniak 20:4:1) und Ausrühren mit Wasser und nachfolgend Ethanol 0,45 g (43% der Theorie) der Titelverbindung vom Schmp. 18G-181°C (Zersetzung).According to Example 1, 1-g (2.5 mmol) of 2,2-difluoro-6- [3-methyl-4-pyrrolidinyl- (1) -pyridyl- (2) -methylthio] -5H- [1,3 ] -dioxolo- [4,5-f] benzimidazole after chromatography on silica gel (eluent: ethyl acetate / ethanol / concentrated ammonia 20: 4: 1) and stirring with water and subsequently ethanol 0.45 g (43% of theory) Title compound of mp 18G-181 ° C (decomposition).
Entsprechend Beispiel 1 erhält man außerdem 2-[4-Dimethylamino-3-methylpyridyl-(2)-methylsulfinyl]-5-(1,1,2,2- tetrafluorethoxy)-1H-benzimidazol,According to Example 1, 2- [4-dimethylamino-3-methylpyridyl- (2) -methylsulfinyl] -5- (1,1,2,2-tetrafluoroethoxy) -1H-benzimidazole is also obtained,
2-[3-Methyl-4-nnorpholinopyridyl-(2)-methylsulfinyl]-5-(1,1,2,2-tetrafluorethoxy)-1H-benzimidazol, Schmp. 80°C (Zersetzung), und 5-Difluormethoxy-2-[3-methyl-4-pyrrolidinyl-(1)-pyridyl-(2)-methylsul- finyl]-1H-benzimidazol, Schrnp. 182- 183°C (Zersetzung), durch Oxidation von2- [3-Methyl-4-nnorpholinopyridyl- (2) -methylsulfinyl] -5- (1,1,2,2-tetrafluoroethoxy) -1H-benzimidazole, mp. 80 ° C (decomposition), and 5-difluoromethoxy- 2- [3-methyl-4-pyrrolidinyl- (1) -pyridyl- (2) -methylsulfinyl] -1H-benzimidazole, no. 182 - 183 ° C (decomposition), by oxidation of
2-[4-Dimethylamirιo-3-methylpyridyl-(2)-methylthio]-5-(1,1,2,2-tetra- fluorethoxy)-1H-benzimidazol,2- [4-Dimethylamirιo-3-methylpyridyl- (2) -methylthio] -5- (1,1,2,2-tetra-fluoroethoxy) -1H-benzimidazole,
2-[3-Methyl-4-morpholinopyridyl-(2)-methylthio]-5-(1,1,2,2-tetrafluor- ethoxy)-1H-benzimidazol und 5-Difluormethoxy-2-[3-methyl-4-pyrrolidinyl (1)-pyridyl-(25-methyl- thio]-1H-benzimidazol mit m-Chlorperoxybenzoesaure.2- [3-Methyl-4-morpholinopyridyl- (2) -methylthio] -5- (1,1,2,2-tetrafluoroethoxy) -1H-benzimidazole and 5-difluoromethoxy-2- [3-methyl-4 -pyrrolidinyl (1) -pyridyl- (25-methyl-thio] -1H-benzimidazole with m-chloroperoxybenzoic acid.
6. 6-[4-Dimethylaminopyridyl-(2)-methylthio]-2.2-difluor-5H-[1.3] dioxolo[4,5-f]benzimidazol6. 6- [4-Dimethylaminopyridyl- (2) methylthio] -2,2-difluoro-5H- [1.3] dioxolo [4,5-f] benzimidazole
Eine Suspension von 2,9 g (12,5 mmol) 2,2-Difluor-5H-[1,3]dioxolo- [4,5-f]benzimidazol-5-thiol und 2,6 g (12,6 mmol) 2-Chlormrthyl-4- dimethylaminopyrldin-hydrochlorid in 140 ml Propanol-(2) wird 2,5 h unter Rückfluß erhitzt. Dabei tritt zeitweise Lösung ein; nach 30 Min. fällt jedoch wieder ein Niederschlag aus. Dieser wird abgesaugt, zwischen konzentrierter Natriumcarbonatlösung und Chloroform verteilt, die organische Phase gewaschen, getrocknet und eingeengt. Man erhält 3,9 g (85% der Theorie) farblose Kristalle vom Schmp. 211-213°C.A suspension of 2.9 g (12.5 mmol) of 2,2-difluoro-5H- [1,3] dioxolo- [4,5-f] benzimidazole-5-thiol and 2.6 g (12.6 mmol ) 2-chloromethyl-4- dimethylaminopyrldine hydrochloride in 140 ml of propanol (2) is heated under reflux for 2.5 h. At times there is a solution; after 30 minutes, however, a precipitate falls out again. This is suction filtered, partitioned between concentrated sodium carbonate solution and chloroform, the organic phase is washed, dried and concentrated. 3.9 g (85% of theory) of colorless crystals with a melting point of 211-213 ° C. are obtained.
Durch analoge Umsetzung vonBy analogous implementation of
5-Trifluormethoxy-1H-benzimidazol-2-thiol, 5-Difluormethoxy-6-methoxy-1H-benzimidazol-2-thiol,5-trifluoromethoxy-1H-benzimidazole-2-thiol, 5-difluoromethoxy-6-methoxy-1H-benzimidazole-2-thiol,
5-Difluormethoxy-1H-benzimidazol-2-thiol,5-difluoromethoxy-1H-benzimidazole-2-thiol,
5-(1,1,2,2-Tetrafluorethoxy)-1H-benzimidazol-2-thiol und5- (1,1,2,2-tetrafluoroethoxy) -1H-benzimidazole-2-thiol and
6,6,7-Trifluor-6,7-dihydro-1H-[1,4]-dioxino[2,3-f]benzimidazol-2-thiol mit 2-Chlormethyl-4-dlmethylaminopyridin-hydrochlorld erhält man 2-[4-Dimethylamino-pyridyl-(2)-methylthio]-5-trifluormethoxy-1H-benz- imidazol,6,6,7-trifluoro-6,7-dihydro-1H- [1,4] -dioxino [2,3-f] benzimidazole-2-thiol with 2-chloromethyl-4-dlmethylaminopyridine hydrochloride gives 2- [ 4-dimethylamino-pyridyl- (2) -methylthio] -5-trifluoromethoxy-1H-benzimidazole,
5-Difluormethoxy-2-[4-dlmethylamino-pyridyl-(2)-methylthio]-6-methoxy-5-difluoromethoxy-2- [4-dlmethylamino-pyridyl- (2) -methylthio] -6-methoxy-
1H-benzimidazol,1H-benzimidazole,
5-Difluormethoxy-2-[4-dimethylamino-pyridyl-(2)-methylthio]-1H-benzimidazol,5-difluoromethoxy-2- [4-dimethylamino-pyridyl- (2) -methylthio] -1H-benzimidazole,
2-[4-Dimethylamino-pyridyl-(2)-methylthio]-5-(1,1,2,2-tetrafluor- ethoxy]-1H-benzimidazol und2- [4-Dimethylamino-pyridyl- (2) -methylthio] -5- (1,1,2,2-tetrafluoroethoxy] -1H-benzimidazole and
2-[4-Dimethylamino-pyridyl-(2)-methylthio]-6,6,7-trifluor-6,7-dihydro-2- [4-dimethylamino-pyridyl- (2) -methylthio] -6,6,7-trifluoro-6,7-dihydro-
1 H-[ 1 , 4 ] -dioκino[ 2 , 3-f]benzimidazol .1 H- [1, 4] -dioκino [2, 3-f] benzimidazole.
Durch analoge Umsetzung vonBy analogous implementation of
5 -Trifluormethoxy-1 H-benzimidazol-2-thiol,5-trifluoromethoxy-1 H-benzimidazole-2-thiol,
5-Difluormethoxy-6-methoxy- 1 H-benzimidazol-2-thiol,5-difluoromethoxy-6-methoxy-1 H -benzimidazole-2-thiol,
5-Difluormethoxy- 1 H-benzimidazol-2-thiol und 2 , 2-Difluor-5H-[ 1 , 3 ]-dioxolo[ 4 , 5-f] benzimidazol-6-thiol mit 2-Chlormethyl-4-dimethylamino-6-methyl-pyridin-hydrochlorid erhält man5-difluoromethoxy-1 H -benzimidazole-2-thiol and 2,2-difluoro-5H- [1,3] -dioxolo [4,5-f] benzimidazole-6-thiol with 2-chloromethyl-4-dimethylamino-6 -methyl-pyridine hydrochloride is obtained
2-[4-Dimethylamino-6-methyl-pyridyl-(2)-methylthio]-5-trifluormethoxy- 1H-benzimidazol, 5-Difluormethoxy-2-[4-dimethylamino-6-methyl-pyridyl-(2)-methylthlo]-2- [4-Dimethylamino-6-methyl-pyridyl- (2) -methylthio] -5-trifluoromethoxy-1H-benzimidazole, 5-difluoromethoxy-2- [4-dimethylamino-6-methyl-pyridyl- (2) -methylthlo ] -
6-methoxy-1H-benzimidazol,6-methoxy-1H-benzimidazole,
5-Difluormethoxy-2-[4-dimethylamino-6-methyl-pyridyl-(2)-methylthio]- 1H-benzimidazol und 6-[4-Dimethylamino-6-methyl-pyridyl-(2)-methylthio]-2,2-dlfluor-5H- [1,3]-dioxolo[4,5-f]benzimidazol.5-difluoromethoxy-2- [4-dimethylamino-6-methyl-pyridyl- (2) -methylthio] - 1H-benzimidazole and 6- [4-Dimethylamino-6-methyl-pyridyl- (2) -methylthio] -2,2-dlfluoro-5H- [1,3] -dioxolo [4,5-f] benzimidazole.
Durch analoge Umsetzung von 5- ( 1 , 1 ,2,2-Tetrafluorethoxy)-1H-benzimidazol-2-thlol,By analogous reaction of 5- (1, 1, 2,2-tetrafluoroethoxy) -1H-benzimidazol-2-thlol,
6i6,7-Trifluor-6,7-dihydro-1H-[1,4]-dioxino[2,3-f]benzlmidazol-2-thiol und6i6,7-trifluoro-6,7-dihydro-1H- [1,4] -dioxino [2,3-f] benzlmidazole-2-thiol and
2,2-Difluor-5H-[1,3]-dioxolo[4,5-f]benzimidazol-6-thiol mit 2-Chlormethyl-4-methylamino-pyridin-hydrochlorid erhält man2,2-difluoro-5H- [1,3] -dioxolo [4,5-f] benzimidazole-6-thiol with 2-chloromethyl-4-methylamino-pyridine hydrochloride is obtained
2-[4-Methylamino-pyridyl-(2)-methylthio]-5-(1,1,2,2-tetrafluorethoxy)-2- [4-methylamino-pyridyl- (2) -methylthio] -5- (1,1,2,2-tetrafluoroethoxy) -
1H-benzimidazol,1H-benzimidazole,
6,6,7-Trifluor-2-[4-methylamino-pyridyl-(2)-methylthio]-6,7-dihydro-1H-6,6,7-trifluoro-2- [4-methylamino-pyridyl- (2) -methylthio] -6,7-dihydro-1H-
[1,4]-dioxlno[2,3-f]benzimidazol und 2,2-Difluor-6-[4-methylamino-pyridyl-(2)-methylthio]-5H-[1,3]-dioxolo-[1,4] -dioxlno [2,3-f] benzimidazole and 2,2-difluoro-6- [4-methylamino-pyridyl- (2) -methylthio] -5H- [1,3] -dioxolo-
[4,5-f]benzimidazol.[4,5-f] benzimidazole.
Durch analoge Umsetzung vonBy analogous implementation of
5-Trifluormethoxy-1H-benzimidazol-2-thiol, 5-Difluormethoxy-6-methoxy-1H-benzimidazol-2-thiol und5-trifluoromethoxy-1H-benzimidazole-2-thiol, 5-difluoromethoxy-6-methoxy-1H-benzimidazole-2-thiol and
2,2-Difluor-5H-[1,3]-dioxolo[4,5-f]benzimidazol-6-thiol mit 2-Chlormethyl-4-morpholino-pyridin-hydrochlorld erhält man2,2-difluoro-5H- [1,3] -dioxolo [4,5-f] benzimidazole-6-thiol with 2-chloromethyl-4-morpholino-pyridine hydrochloride is obtained
2-[4-Morpholino-pyridyl-(2)-methylthio]-5-trifluormethoxy-1H-benzimidazol,2- [4-morpholino-pyridyl- (2) -methylthio] -5-trifluoromethoxy-1H-benzimidazole,
5-Difluormethoxy-6-methoxy-2-[4-morpholino-pyridyl-(2)-methylthio]-1H- benzimidazol und5-difluoromethoxy-6-methoxy-2- [4-morpholino-pyridyl- (2) -methylthio] -1H-benzimidazole and
2,2-Difluor-6-[4-morphollno-pyridyl-(2)-methylthio]-5H-[1,3]-dioxolo-2,2-difluoro-6- [4-morphollno-pyridyl- (2) -methylthio] -5H- [1,3] -dioxolo-
[4, 5-f]benzimidazol.[4,5-f] benzimidazole.
Durch analoge Umsetzung vonBy analogous implementation of
2,2-Difluor-5H-[1,3]-dioxolo[4,5-f]benzimidazol-6-thiol mit 4-Acetylamino-2-chlormethyl-pyridin-hydrochlorid erhält man 6-[4-Acetylamino-pyridyl-(2)-methylthio]-2,2-difluor-5H-[1,3]-dioxolo-2,2-difluoro-5H- [1,3] dioxolo [4,5-f] benzimidazole-6-thiol with 4-acetylamino-2-chloromethyl-pyridine hydrochloride gives 6- [4-acetylamino-pyridyl- (2) -methylthio] -2,2-difluoro-5H- [1,3] -dioxolo-
[4,5-f]benzimidazol. 7. 6-[4-Dlmethylamlno-3-methylpyridyl-(2)-methylthio1-2.2-difluor-5H- [1.3]-dioxolo[4.5-fIbenzimidazol[4,5-f] benzimidazole. 7. 6- [4-Dimethylamlno-3-methylpyridyl- (2) -methylthio1-2.2-difluoro-5H- [1.3] -dioxolo [4.5-f-benzimidazole
Zu einer Suspension von 4,5 g (19,5 mmol) 2 , 2-Difluor-5H-[1,3]-dioxolo- [4,5-f]benzimidazol-6-thiol und 4,3 g (19,5 mmol) 2-Chlormethyl-4-di- methylamino-3-methylpyridin-hydrochlorid in 200 ml Methanol tropft man bei Raumtemperatur 8 ml (40 mmol) Natriummethylatlösung und rührt noch weitere 0,5 h. Zur Aufarbeitung wird die entstandene Lösung mit Wasser versetzt und mehrfach mit Chloroform extrahiert. Die organischen Phasen werden gewaschen, getrocknet und im Vakuum eingeengt. Der zähflüssige Rückstand wird mit Diethylether zur Kristallisation gebracht. Nach Umkristallisation aus Propanol-(2) erhält man 6,3 g (85% der Theorie) der Titelverbindung vom Schmp. 192-193°C.To a suspension of 4.5 g (19.5 mmol) 2,2-difluoro-5H- [1,3] dioxolo- [4,5-f] benzimidazole-6-thiol and 4.3 g (19, 5 mmol) of 2-chloromethyl-4-dimethylamino-3-methylpyridine hydrochloride in 200 ml of methanol is added dropwise at room temperature to 8 ml (40 mmol) of sodium methylate solution and stirred for a further 0.5 h. For working up, the resulting solution is mixed with water and extracted several times with chloroform. The organic phases are washed, dried and concentrated in vacuo. The viscous residue is crystallized with diethyl ether. After recrystallization from propanol (2), 6.3 g (85% of theory) of the title compound of mp. 192-193 ° C.
8. 2-[4-Dimethylamino-3-methylpyridyl-(2)-methylthiol-5-(1.1.2.2- tetrafluorethoxy)-1H-benzimidazol8. 2- [4-Dimethylamino-3-methylpyridyl- (2) -methylthiol-5- (1.1.2.2-tetrafluoroethoxy) -1H-benzimidazole
Analog Beispiel 7 erhält man aus 7,7 g (29 mmol) 5-(1,1,2,2-Tetrafluor- ethoxy)-1H-benzimidazol-2-thiol und 6,4 g (29 mmol) 2-Chlormethyl-4-di- methylamino-3-methylpyridin-hydrochlorid nach ehrαmatographischer Reinigung (Kieselgel, Dichlormethan/Methanol 13:1) 7,5 g (62% der Theorie) der Titelverbindung vom Schmp. 63-65°C.Analogously to Example 7, from 7.7 g (29 mmol) of 5- (1,1,2,2-tetrafluoroethoxy) -1H-benzimidazole-2-thiol and 6.4 g (29 mmol) of 2-chloromethyl- 4-dimethylamino-3-methylpyridine hydrochloride after Ehrαmatographic cleaning (silica gel, dichloromethane / methanol 13: 1) 7.5 g (62% of theory) of the title compound of mp. 63-65 ° C.
9. 5-Difluormethoxy-2-[3-methyl-4-moroholinoDyridyl-(2)-methylthio]- 1H-benzimidazol9. 5-Difluoromethoxy-2- [3-methyl-4-moroholinoDyridyl- (2) methylthio] -1H-benzimidazole
Analog Beispiel 6 erhält man aus 3 g (13,88 mmol) 5-Difluormethoxy- 1H- benzimidazol-2-thiol und 3,65 g (13,87 mmol) 2-Chlormethyl-3-methyl-4- morpholinopyridin-hydrochlorid 5,32 g (94% der Theorie) der Titelverbindung vom Schmp. 75-78°C (unter Sintern).Analogously to Example 6, 3 g (13.88 mmol) of 5-difluoromethoxy-1H-benzimidazole-2-thiol and 3.65 g (13.87 mmol) of 2-chloromethyl-3-methyl-4-morpholinopyridine hydrochloride 5 are obtained , 32 g (94% of theory) of the title compound of mp. 75-78 ° C (with sintering).
1H-NMR(CDCl3) : 2,3 ppm (3-CH3,s,3H); 3,0 ppm (N-CH2,t,4H); 3,9 ppm (O-CH2, t,4H); 4,4 ppm (S-CH2,S,2H); 6.1-6.9 ppm (CF2H,t,1H); 6,85 ppm (PyH-5,d,1H); 6,95-7,0 ppm (H-7,d,1H); 7,3 ppm (H-4,s,1H); 7,45-7,5 ppm (H-6,d,1H); 8,35 ppm (PyH-6,d,1H). 10. 2-[3-Methyl-4-morpholinopyridyl- ( 2 ) -methylthio1 -5- ( 1 , 1 , 2 , 2-tetra- fluorethoxyl - 1 H-benzlmidazol 1 H NMR (CDCl 3 ): 2.3 ppm (3-CH 3 , s, 3H); 3.0 ppm (N-CH 2, t, 4H); 3.9 ppm (O-CH 2 , t, 4H); 4.4 ppm (S-CH 2 , S, 2H); 6.1-6.9 ppm (CF 2 H, t, 1H); 6.85 ppm (PyH-5, d, 1H); 6.95-7.0 ppm (H-7, d, 1H); 7.3 ppm (H-4, s, 1H); 7.45-7.5 ppm (H-6, d, 1H); 8.35 ppm (PyH-6, d, 1H). 10. 2- [3-Methyl-4-morpholinopyridyl- (2) -methylthio1 -5- (1, 1, 2, 2-tetrafluoroethoxyl - 1 H -benzlmidazole
Analog Beispiel 6 erhält man aus 2,6 g (9,9 mmol) 5-(1,1,2,2-Tetra- fluorethoxy)-1H-benzimidazol-2-thiol und 2,6 g (9,9 mmol) 2-Chlor- methyl-3-methyl-4-morpholinopyridin-hydrochlorid 3,5 g (73% der Theorie) der Titelverbindung vom Schmp. 78-85°C. 1H-NMR(CDCl3) : 2,36 ppm (3-CH3,s,3H); 2,9-3,1 ppm (N-CH2, t, 4H) ; 3,9 ppm (O-CH2,t,4H) ; 4,39 ppm (CH2,s,2H); 5,6-6,2 ppm ( CF2H,m, 1H ) ; 6,9 ppm (PyH-5,d,1H) ; 7,05 ppm (H-7,d,1H); 7,3 ppm (H-4,s,1H); 7,45 ppm (H-6,d,1H); 8,35 ppm (PyH-6 ,d , 1H) ; 12,64 ppm (NH, breit).Analogously to Example 6, 2.6 (9.9 mmol) of 5- (1,1,2,2-tetrafluoroethoxy) -1H-benzimidazole-2-thiol and 2.6 g (9.9 mmol) are obtained. 2-chloromethyl-3-methyl-4-morpholinopyridine hydrochloride 3.5 g (73% of theory) of the title compound of mp. 78-85 ° C. 1H NMR (CDCl 3 ): 2.36 ppm (3-CH 3 , s, 3H); 2.9-3.1 ppm (N-CH 2 , t, 4H); 3.9 ppm (O-CH 2 , t, 4H); 4.39 ppm (CH 2 , s, 2H); 5.6-6.2 ppm (CF 2 H, m, 1H); 6.9 ppm (PyH-5, d, 1H); 7.05 ppm (H-7, d, 1H); 7.3 ppm (H-4, s, 1H); 7.45 ppm (H-6, d, 1H); 8.35 ppm (PyH-6, d, 1H); 12.64 ppm (NH, broad).
11. 2.2-Difluor-6-[3-methyl-4-morpholinooyridyl-(2)-methylthio1-5H- [1.3]-dioxolo[4.5-fIbenzimidazol11. 2,2-difluoro-6- [3-methyl-4-morpholinooyridyl- (2) -methylthio1-5H- [1.3] -dioxolo [4.5-f-benzimidazole
Analog Beispiel 6 erhält man aus 6,5 g (28,2 mmol) 2, 2-Difluor-5H- [1,3]-dioxolo[4,5-f]benzimidazol-6-thiol und 7,4 g (28,2 mmol) 2-Chlor- methyl-3-methyl-4-morpholinopyridin-hydrochlorid 10,5 g (88% der Theorie) der Titelverbindung vom Schmp. 178-179°C.Analogously to Example 6, 2,2 g (28.2 mmol) of 2,2-difluoro-5H- [1,3] dioxolo [4,5-f] benzimidazole-6-thiol and 7.4 g (28 , 2 mmol) 2-chloromethyl-3-methyl-4-morpholinopyridine hydrochloride 10.5 g (88% of theory) of the title compound of mp. 178-179 ° C.
12. 2.2-Difluor-6-[3-methyl-4-Dyrrolidinyl-(1)-pyridyl-(2)-methyl- thio]-5H-[1.3]-dioxolo[4.5-fIbenzimidazol12. 2,2-Difluoro-6- [3-methyl-4-Dyrrolidinyl- (1) pyridyl- (2) methylthio] -5H- [1.3] dioxolo [4.5-fbenzimidazole
Analog Beispiel 7 erhält man aus 2,8 g (12 mmol) 2,2-Difluor-5H-[1,33- dioxolo[4,5-f]benzimidazol-6-thiol und 3 g (12 mmol) 2-Chlormethyl-3- methyl-4-pyrrolidinyl-(1)-pyridin-hydrochlorid 1,2 g (25% der Theorie) der Titelverbindung vom Schmp. 178-180°C (Zersetzung).Analogously to Example 7, 2.8 g (12 mmol) of 2,2-difluoro-5H- [1,33-dioxolo [4,5-f] benzimidazole-6-thiol and 3 g (12 mmol) of 2-chloromethyl are obtained -3-methyl-4-pyrrolidinyl- (1) pyridine hydrochloride 1.2 g (25% of theory) of the title compound of mp. 178-180 ° C (decomposition).
Analog erhält manYou get analog
5-Difluormethoxy-2-[3-methyl-4-pyrrolidinyl- ( 1 )-pyridyl-(2)-methyl- thio]-1H-benzimidazol (Schmp.: Fumarat 105-108°C) aus 5-Difluor- methoxy-1H-benzimidazol-2-thiol und 2-Chlormethyl-3-methy1-4-pyrrolidinyl-(1)-pyridin-hydrochlorid. Ausoangsverblndungen5-difluoromethoxy-2- [3-methyl-4-pyrrolidinyl- (1) -pyridyl- (2) -methylthio] -1H-benzimidazole (mp .: fumarate 105-108 ° C.) from 5-difluoromethoxy -1H-benzimidazole-2-thiol and 2-chloromethyl-3-methy1-4-pyrrolidinyl- (1) -pyridine hydrochloride. External blinding
A. PvridineA. Pvridine
A1. 2-Chlormethyl-4-dimethylamlnoDyrldln-hvdrochloridA1. 2-chloromethyl-4-dimethylamlnoDyrldln-hydrochloride
Zu einer auf -20°C abgekühlten Lösung von 4,4 g (28,9 mmol) 4-Dimethyl- amino-2-hydroxymethylpyridin in 70 ml Dichlormethan tropft man während 30 Min. 4,25 ml (57,8 mmol) Thionylchlorid und rührt noch 1 h bei dieser Temperatur sowie ca. 17 h bei Raumtemperatur nach. Nach Entfernen der flüchtigen Bestandteile im Vakuum erhält man 5,8 g (97% der Theorie) leicht beige Kristalle vom Schmp. 188-197°C. 1H-NMR (DMS0-d6): 3,2 ppm (s, 6H); 4,9 ppm (s, 2H); 6,8-7,0 ppm (m, 1H); 7,25 ppm (d, 1H); 8,2 ppm (d, 1H);4.25 ml (57.8 mmol) of thionyl chloride are added dropwise to a solution of 4.4 g (28.9 mmol) of 4-dimethylamino-2-hydroxymethylpyridine in 70 ml of dichloromethane, cooled to -20 ° C., over 30 minutes and stirred for a further 1 h at this temperature and for about 17 h at room temperature. After removal of the volatile constituents in vacuo, 5.8 g (97% of theory) of slightly beige crystals of mp. 188-197 ° C. are obtained. 1H-NMR (DMS0-d 6 ): 3.2 ppm (s, 6H); 4.9 ppm (s, 2H); 6.8-7.0 ppm (m, 1H); 7.25 ppm (d, 1H); 8.2 ppm (d, 1H);
A2. 2-Chlormethyl-4-methylaminooyridin-hvdrochloridA2. 2-chloromethyl-4-methylaminooyridine hydrochloride
Entsprechend Beispiel A1 erhält man aus 5 g (36,2 mmol) 2-Hydroxy- methyl-4-methylaminopyridin 6,8 g (97% der Theorie) 2-Chlormethyl-4- methylaminopyridin-hydrochlorid vom Schmp. 171-173°C.According to Example A1, 6.8 g (97% of theory) of 2-chloromethyl-4-methylaminopyridine hydrochloride, mp. 171-173 ° C., are obtained from 5 g (36.2 mmol) of 2-hydroxymethyl-4-methylaminopyridine .
A3. 2-Chlormethyl-4-moroholinoDyridin-hvdrochloridA3. 2-chloromethyl-4-moroholinoDyridine hydrochloride
Entsprechend Beispiel A1 erhält man aus 1,7 g (8,75 mmol) 2-Hydroxy- methyl-4-morpholinopyridin 1,3 g (60% der Theorie) 2-Chlormethyl-4- morpholinopyridin-hydrochlorid vom Schmp. 212-215°C (Zersetzung).According to Example A1, 1.7 g (8.75 mmol) of 2-hydroxymethyl-4-morpholinopyridine gave 1.3 g (60% of theory) of 2-chloromethyl-4-morpholinopyridine hydrochloride, mp 212-215 ° C (decomposition).
A4. 2-Chlormethyl-4-dimethylamino-6-methylDyridin-hvdrochloridA4. 2-chloromethyl-4-dimethylamino-6-methyldyridine hydrochloride
Entsprechend Beispiel A1 erhält man aus 5,6 g (33,7 mmol) 4-Dimethyl- amino-2-hydroxymethyl-6-methylpyridin 7,4 g (99% der Theorie) farbloses 2-Chlormethyl-4-dimethylamino-6-methylpyridin-hydrochlorid vom Schmp. 162-168°C.According to Example A1, 7.4 g (99% of theory) of colorless 2-chloromethyl-4-dimethylamino-6- is obtained from 5.6 g (33.7 mmol) of 4-dimethylamino-2-hydroxymethyl-6-methylpyridine. methylpyridine hydrochloride, mp. 162-168 ° C.
1H-NMR(DMS0-d6) : 2,56 ppm (verbreitertes s, 3H); 3,20 ppm (s, 6H); 4,95 ppm (s, 2H); 6,6 ppm (d, 1H); 7,18 ppm (d, 1H) A5. 4-Acetvlamlno-2-chlormethvlpvridln-hvdrochlorid 1 H NMR (DMS0-d 6 ): 2.56 ppm (broadened s, 3H); 3.20 ppm (s, 6H); 4.95 ppm (s, 2H); 6.6 ppm (d, 1H); 7.18 ppm (d, 1H) A5. 4-Acetvlamlno-2-chloromethvlpvridln-hydrochloride
Entsprechend Beispiel A1 erhält man aus 3,17 g (19,1 mmol) 4-Acetyl- amino-2-hydroxymethylpyridin 4 g (ca. 95% der Theorie) des sehr hygroskopischen 4-Acetylamino-2-chlormethylpyridin-hydrochlorids. Schmp. ca. 140°C.According to Example A1, 4 g (approx. 95% of theory) of the very hygroscopic 4-acetylamino-2-chloromethylpyridine hydrochloride is obtained from 3.17 g (19.1 mmol) of 4-acetylamino-2-hydroxymethylpyridine. 140 ° C.
1H-NMR(DMSO-d6): 2,24 ppm (s, 3H); 5,07 ppm (s, 2H); 8,05 ppm (dd, 1H); 8,29 ppm (d, 1H); 8,7 ppm (d, 1H); 11,9 ppm (verbr. s, ca. 1H). 1 H NMR (DMSO-d 6 ): 2.24 ppm (s, 3H); 5.07 ppm (s, 2H); 8.05 ppm (dd, 1H); 8.29 ppm (d, 1H); 8.7 ppm (d, 1H); 11.9 ppm (spent s, approx. 1H).
A6. 4-Acetylamino-2-hvdroκvmethylpyrldinA6. 4-acetylamino-2-hvdroκvmethylpyrldin
Eine Lösung von 16,12 g (77,4 mmol) 2-Acetoxymethyl-4-acetylamino- pyridin und 6 g (150 mmol) Natriumhydroxid in 100 ml 90%igem Ethanol wird 5 h bei 90°C gerührt. Nach dem Abkühlen wird auf pH 9 gestellt und zur Trockene eingeengt. Der Rückstand wird zuerst mit Methanol und danach mit Aceton mehrmals ausgerührt. Die organischen Extrakte werden wiederum eingeengt und der Rückstand an neutralem Kieselgel mit dem Elutionsgemisch Dichlormethan/Methanol 13:1 säulenchromatographiert. Man erhält 7 g (59% der Theorie) gelbliche Kristalle vom Schmp. 171-173°C (Umkristallisation aus Wasser).A solution of 16.12 g (77.4 mmol) of 2-acetoxymethyl-4-acetylaminopyridine and 6 g (150 mmol) of sodium hydroxide in 100 ml of 90% ethanol is stirred at 90 ° C. for 5 h. After cooling, it is adjusted to pH 9 and concentrated to dryness. The residue is stirred several times first with methanol and then with acetone. The organic extracts are again concentrated and the residue is column chromatographed on neutral silica gel with the elution mixture dichloromethane / methanol 13: 1. 7 g (59% of theory) of yellowish crystals of mp. 171-173 ° C. (recrystallization from water) are obtained.
A7. 2-Acetoxymethyl-4-acetylaminopyridinA7. 2-acetoxymethyl-4-acetylaminopyridine
Eine Mischung von 15,8 g (0,127 mol) 4-Amino-2-methylpyridin-N-oxid und 45 ml Acetanhydrid wird in ein auf 110°C vorgeheiztes Ölbad gebracht. Die allmählich einsetzende exotherme Reaktion wird durch zeitweisesA mixture of 15.8 g (0.127 mol) of 4-amino-2-methylpyridine-N-oxide and 45 ml of acetic anhydride is placed in an oil bath preheated to 110 ° C. The gradually starting exothermic reaction is temporarily
Entfernen des Bades gesteuert. Nach Abklingen der Reaktion wird noch 1h bei 110°C gerührt und danach im Vakuum eingeengt. Der Rückstand wird an neutralem Kieselgel mit dem Elutionsgemisch Dichlormethan/Methanol 13:1 säulenchromatographiert. Ausbeute: 14,8 g (56% der Theorie) teilweise kristallisierendes öl.Controlled removal of the bath. After the reaction has subsided, the mixture is stirred for a further 1 h at 110 ° C. and then concentrated in vacuo. The residue is column chromatographed on neutral silica gel with the elution mixture dichloromethane / methanol 13: 1. Yield: 14.8 g (56% of theory) of partially crystallizing oil.
1H-NMR (CDCl3): 2,11 ppm (s, 3H); 2,20 ppm (s, 3H); 5,18 ppm (s, 2H) ; 7,43 ppm (dd, 1H); 7,67 ppm (d, 1H); 8,45 ppm (d, 1H); 9,1 ppm (verbreit, s, 1H). 1 H NMR (CDCl 3 ): 2.11 ppm (s, 3H); 2.20 ppm (s, 3H); 5.18 ppm (s, 2H); 7.43 ppm (dd, 1H); 7.67 ppm (d, 1H); 8.45 ppm (d, 1H); 9.1 ppm (widespread, s, 1H).
4-Amino-2-methylpyridin-N-oxid ist in Farmaco, Ed. Sei. 22, 99 (1967) beschrieben. A8. 2-Chlormethvl-4-dimethvlamino-3-methvlpvridin-hvdrochlorid4-Amino-2-methylpyridine-N-oxide is available in Farmaco, Ed. Be. 22, 99 (1967). A8. 2-chloromethylene-4-dimethlamino-3-methylene chloride-hydrochloride
Entsprechend Beispiel A1 erhält man aus 3 g (18 mmol) 4-Dimethylamino- 2-hydroxymethyl-3-methylpyridin 1,9 g (48% der Theorie) 2-Chlormethyl- 4-dimethylamino-3-methylpyridin-hydrochlorid vom Schmp. 197-199°C.According to Example A1, 3 g (18 mmol) of 4-dimethylamino-2-hydroxymethyl-3-methylpyridine gave 1.9 g (48% of theory) of 2-chloromethyl-4-dimethylamino-3-methylpyridine hydrochloride, mp 197 -199 ° C.
A9. 2-Chlormethyl-3-methyl-4-moroholinooyridin-hvdrochloridA9. 2-chloromethyl-3-methyl-4-moroholinooyridine hydrochloride
Entsprechend Beispiel A1 erhält man aus 20 g (96 mmol) 2-Hydroxy- methyl-3-methyl-4-morpholinopyridin 23,7 g (94% der Theorie) 2-Chlor- methyl-3-methyl-4-morpholinopyridin-hydrochlorid vom Schmp. 77-80°C.According to Example A1, 23.7 g (94% of theory) of 2-chloromethyl-3-methyl-4-morpholinopyridine hydrochloride are obtained from 20 g (96 mmol) of 2-hydroxymethyl-3-methyl-4-morpholinopyridine from mp. 77-80 ° C.
A10. 2-Chlormethyl-3-methyl-4-oyrrolidinyl-(1)-oyridin-hvdrochloridA10. 2-chloromethyl-3-methyl-4-oyrrolidinyl- (1) -oyridine hydrochloride
Entsprechend Beispiel A1 erhält man aus 11 g (57 mmol) 2-Hydroxymethyl- 3-methyl-4-pyrrolidinyl-(1)-pyridin 3,5 g (25% der Theorie) 2-Chlor- methyl-3-methyl-4-pyrrolidinyl-(1)-pyridin-hydrochlorid vom Schmp. 88-90°C. Die Substanz ist hygroskopisch.According to Example A1, 11 g (57 mmol) of 2-hydroxymethyl-3-methyl-4-pyrrolidinyl- (1) -pyridine gave 3.5 g (25% of theory) of 2-chloromethyl-3-methyl-4 -pyrrolidinyl- (1) -pyridine hydrochloride of mp. 88-90 ° C. The substance is hygroscopic.
All. 4-Dimethylamino-2-hvdroxymethyl-3-methylpyridinAlles. 4-dimethylamino-2-hvdroxymethyl-3-methylpyridine
50 g (0,3 mol) 4-Dimethylamino-2,3-dimethylpyridin-N-oxyd werden bei Raumtemperatur in 300 ml Acetanhydrid eingetropft und die entstandene Lösung noch 1 h bei Raumtemperatur gerührt. Das gebildete 2-Acetoxy- methyl-4-dimethylamino-3-methylpyridin wird nach Abdestillieren des überschüssigen Acetanhydrids im Vakuum durch Verrühren mit ca. 300 ml verdünnter Natriumhydroxydlösung (30 Min. bei Raumtemperatur) in das 4-Dimethylamino-2-hydroxymethyl-3-methylpyridin übergeführt. Ausbeute: 34 g (ca. 68% der Theorie) als öl. Schmp. des Monohydro- Chlorids: 173-175°C (aus Isopropanol/Cyclohexan).50 g (0.3 mol) of 4-dimethylamino-2,3-dimethylpyridine-N-oxide are added dropwise in 300 ml of acetic anhydride at room temperature and the resulting solution is stirred for a further 1 h at room temperature. The 2-acetoxy-methyl-4-dimethylamino-3-methylpyridine formed is, after distilling off the excess acetic anhydride in vacuo, by stirring with about 300 ml of dilute sodium hydroxide solution (30 minutes at room temperature) into the 4-dimethylamino-2-hydroxymethyl-3 -methylpyridine transferred. Yield: 34 g (approx. 68% of theory) as an oil. Mp of the monohydrochloride: 173-175 ° C (from isopropanol / cyclohexane).
A12. 2-Hvdroxymethyl-3-methyl-4-pyrrolidinyl-(1)-pyridinA12. 2-hydroxymethyl-3-methyl-4-pyrrolidinyl- (1) pyridine
Eine Lösung von 8 g 2,3-pimethyl-4-pyrrolidinyl-(1)-pyridin-N-oxid inA solution of 8 g 2,3-pimethyl-4-pyrrolidinyl- (1) -pyridine-N-oxide in
100 ml Acetanhydrid wird 30 Min. bei 100°C gerührt. Nach Abdestillieren des überschüssigen Acetanhydrids und Abkühlen wird das gebildete 2-Acetoxymethyl-3-methyl-4-pyrrolidinyl-(1)-pyridin durch halbstündiges Rühren mit ca. 30 ml 6 n Natriumhydroxydlösung bei Raumtemperatur zum100 ml of acetic anhydride is stirred at 100 ° C. for 30 minutes. After distilling off the excess acetic anhydride and cooling, the 2-acetoxymethyl-3-methyl-4-pyrrolidinyl- (1) -pyridine formed is left for half an hour Stir with about 30 ml of 6N sodium hydroxide solution at room temperature
2-Hydroxy-methyl-3-methyl-4-pyrrolidinyl-(1)-pyridin hydrolysiert. Die2-Hydroxy-methyl-3-methyl-4-pyrrolidinyl- (1) -pyridine hydrolyzed. The
Substanz wird durch Extraktion mit Methylenchlorid, Waschen, Trocknen und Eindampfen am Rotationsverdampfer isoliert.The substance is isolated by extraction with methylene chloride, washing, drying and evaporation on a rotary evaporator.
Ausbeute: 6,8 g (85% der Theorie) vom Schmp. 215-217°C (aus Isopropanol).Yield: 6.8 g (85% of theory) of mp. 215-217 ° C (from isopropanol).
2-Hydroxymethyl-3-methyl-4-morpholinopyridin ist in J.Med.Chem. 19, 1209 [1976] erwähnt.2-hydroxymethyl-3-methyl-4-morpholinopyridine is described in J.Med.Chem. 19, 1209 [1976].
A13. 4-Dimethvlamino-2.3-dlmethvlpvridin-N-oxvdA13. 4-Dimethvlamino-2,3-dlmethvlpvridin-N-oxvd
In einem Laborautoklaven mit Teflonauskleidung wird eine Lösung von 60 g (0,38 mol) 4-Chlor-2,3-dimethylpyridin-N-oxyd in 120 ml Methanol und 120 ml Wasser mit 100 mg Kupfer ( Dchlorid und 80 ml Olmethylamin versetzt. Nach Verschließen wird die Mischung 55 h bei 90°C gerührt (Magnetrührer, Druckanstieg bis ca. 10 bar). Nach Abkühlen werden weitere 200 ml Wasser zugegeben und der Ansatz mehrmals mit Chloroform extrahiert. Nach Waschen, Trocknen und Einengen der organischen Phase im Vakuum erhält man 62 g (98% der Theorie) 4-Dimethylamino-2,3-dimethylpyridin-N-oxyd als dickflüssiges öl.A solution of 60 g (0.38 mol) of 4-chloro-2,3-dimethylpyridine-N-oxide in 120 ml of methanol and 120 ml of water is mixed with 100 mg of copper (dchloride and 80 ml of olmethylamine) in a laboratory autoclave with a Teflon lining. After sealing, the mixture is stirred for 55 h at 90 ° C. (magnetic stirrer, pressure rise to about 10 bar) After cooling, a further 200 ml of water are added and the mixture is extracted several times with chloroform, after washing, drying and concentrating the organic phase in vacuo 62 g (98% of theory) of 4-dimethylamino-2,3-dimethylpyridine-N-oxide are obtained as a viscous oil.
1H-NMR (CDCl3): 2,25 ppm (3-CH3 , s ,3H) ; 2,55 ppm (2-CH3 , s ,3H) ; 2,75 ppm [N(CH3)2,s,6H]; 6,75 ppm (5-H,d,1H); 8,1 ppm (6-H,d,1H) 1 H NMR (CDCl 3 ): 2.25 ppm (3-CH 3 , s, 3H); 2.55 ppm (2-CH 3, s, 3H); 2.75 ppm [N (CH 3 ) 2 , s, 6H]; 6.75 ppm (5-H, d, 1H); 8.1 ppm (6-H, d, 1H)
2,3-Dimethyl-4-morpholinopyridin-N-oxyd ist in J.Med.Chem. ü, 1209 (1976) beschrieben.2,3-Dimethyl-4-morpholinopyridine-N-oxide is described in J.Med.Chem. ü, 1209 (1976).
A14. 2.3-Dimethyl-4-pyrrolldlnyl-(1)-oyrldin-N-oxydA14. 2,3-Dimethyl-4-pyrrole dnyl- (1) -oyrldin-N-oxide
Eine Mischung von 10 g (63 mmol) 4-Chlor-2,3-dimethylpyridin-N-oxyd mit 30 g (420 mmol) Pyrrolidin und einer Spatelspitze Kupfer(I)chlocid wird 72 h unter Rückfluß erhitzt. Nach Abkühlen wird mit Wasser versetzt und mehrmals mit Chloroform extrahiert. Die organischen Phasen werden gewaschen, getrocknet und im Vakuum eingeengt. Aus dem flüssigen Rückstand erhält man nach Säulenchromatographie und dem Fließmittel Chloro form/ Methanol 100:3 an Kieselgel 8 g (66t dar Thaorla) 2,3-Dimethyl-4- pyrrolidlnyl-(1)pyridin-N-oxyd vom Schmp. 90-91°C.A mixture of 10 g (63 mmol) of 4-chloro-2,3-dimethylpyridine-N-oxide with 30 g (420 mmol) of pyrrolidine and a spatula tip of copper (I) chlocid is heated under reflux for 72 h. After cooling, water is added and the mixture is extracted several times with chloroform. The organic phases are washed, dried and concentrated in vacuo. The liquid residue gives, after column chromatography and the eluent chloro form / methanol 100: 3 on silica gel 8 g (66 t dar Thaorla) 2,3-dimethyl-4-pyrrolidlnyl- (1) pyridine-N-oxide, mp. 90-91 ° C.
4-Chlor-2,3-dimethylpyridin-N-oxyd ist in J.Med.Chem. 19, 1209 (1976) beschrieben. 4-chloro-2,3-dimethylpyridine-N-oxide is described in J.Med.Chem. 19, 1209 (1976).
B. BenzimldazoleB. Benzimldazole
B1. 5-(1,1,2,2-Tetrafluorethoxy)-1H-benzlmidazol-2-thiolB1. 5- (1,1,2,2-tetrafluoroethoxy) -1H-benzimidazole-2-thiol
a) 55 g 1-Nitro-4-(1,1,2,2-tetrafluorethoxy)benzol werden in 300 ml Ethanol an 0,5 g 10%iger Palladiumkohle in einer Umlaufhydrierungs- apparatur unter Atmosphärendruck 1 h bei 20-45°C hydriert, der Kataly- sator abfiltriert und die Lösung bei 40°C im Vakuum eingeengt. Man verdünnt das 4-(1,1,2,2-tetrafluorethoxy)anilin mit 100 ml Eisessig und tropft 23 ml Essigsäureanhydrid bei Raumtemperatur zu, versetzt nach 30 Min. mit 2 ml Wasser, engt nach kurzer Zeit die Lösung bei 50°C im Vakuum ein und versetzt mit 500 ml Eiswasser. Man erhält 56 g (97t) N-[4-(1,1,2,2-tetrafluorethoxy)phenyl]-acetamid vom Schmp. 121-122°C.a) 55 g of 1-nitro-4- (1,1,2,2-tetrafluoroethoxy) benzene in 300 ml of ethanol on 0.5 g of 10% palladium-carbon in a circulating hydrogenation apparatus under atmospheric pressure for 1 h at 20-45 ° C is hydrogenated, the catalyst is filtered off and the solution is concentrated at 40 ° C. in vacuo. The 4- (1,1,2,2-tetrafluoroethoxy) aniline is diluted with 100 ml of glacial acetic acid and 23 ml of acetic anhydride are added dropwise at room temperature, 2 ml of water are added after 30 minutes and the solution is concentrated at 50 ° C. after a short time in a vacuum and mixed with 500 ml of ice water. 56 g (97t) of N- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -acetamide of mp 121-122 ° C. are obtained.
b) Man löst 55 g der vorstehenden Verbindung in 380 ml Dichlormethan, tropft 55 ml 100%ige Salpetersäure in 10 Min. bei Raumtemperatur zu und rührt noch 6 h. Die organische Lösung wird dann mit wässriger Natrium- carbonatlösung und Wasser gewaschen, mit Magnesiumsulfat getrocknet und eingeengt. Man erhält 65 g (100%) N-[2-Nitro-4-(1,1,2,2-tetrafluorethoxy)phenyl]-acetamid vom Schmp. 80-81°C (aus Cyclohexan).b) 55 g of the above compound are dissolved in 380 ml of dichloromethane, 55 ml of 100% nitric acid are added dropwise in 10 minutes at room temperature and stirring is continued for 6 hours. The organic solution is then washed with aqueous sodium carbonate solution and water, dried with magnesium sulfate and concentrated. 65 g (100%) of N- [2-nitro-4- (1,1,2,2-tetrafluoroethoxy) phenyl] acetamide, mp. 80-81 ° C. (from cyclohexane) are obtained.
c) Man löst 63 g vorstehender Verbindung in 450 ml Methanol, tropft bei Raumtemperatur 106 ml 6 m Natronlauge zu, kühlt im Eisbad und fällt durch Zutropfen von 900 ml Wasser 53 g (98%) 2-Nitro-4-(1,1,2,2-tetra- fluorethoxy)-anilin (Schmp. 85-86°C).c) 63 g of the above compound are dissolved in 450 ml of methanol, 106 ml of 6 M sodium hydroxide solution are added dropwise at room temperature, the mixture is cooled in an ice bath and 53 g (98%) of 2-nitro-4- (1.1 , 2,2-tetrafluoroethoxy) aniline (mp. 85-86 ° C).
d) 33 g vorstehender Verbindung werden in ca. 600 ml Isopropanol an 1 g 10%iger Palladiumkohle in einer Umlaufhydrierungsapparatur drucklos beid) 33 g of the above compound are pressurized in about 600 ml of isopropanol and 1 g of 10% palladium-carbon in a circulating hydrogenation apparatus
Raumtemperatur hydriert. Man saugt den Katalysator ab und fällt mit 4 m Chlorwasserstoff in Ether 34 g (89%) 4-(1,1,2,2-Tetrafluorethoxy)-1,2- phenylendiamin-dihydrochlorid vom Schmp. 275-276°C (Zersetzung).Room temperature hydrogenated. The catalyst is suctioned off and, with 4 M hydrogen chloride in ether, 34 g (89%) of 4- (1,1,2,2-tetrafluoroethoxy) -1,2-phenylenediamine dihydrochloride, mp. 275-276 ° C. (decomposition ).
e) 33 g vorstehender Verbindung werden mit 330 ml Ethanol, 60 ml Wasser, 8,9 g Natriumhydroxid und 23 g Kalium-O-ethyldithiocarbonat (umkristallisiert aus Isopropanol) versetzt und 15 h unter Rückfluß zum Sieden erhitzt. Man versetzt mit 1,2 1 Eiswasser, stellt mit Natron- lauge auf pH 13-14, klärt mit Aktivkohle und fällt mit verdünnter Salzsäure bis pH 3,5. Man erhält 27 g (911) der Titelverbindung vom Schmp. 316-319°C (aus Isopropanol).e) 33 g of the above compound are mixed with 330 ml of ethanol, 60 ml of water, 8.9 g of sodium hydroxide and 23 g of potassium O-ethyldithiocarbonate (recrystallized from isopropanol) and heated to boiling under reflux for 15 h. 1.2 l of ice water are added, and sodium hydroxide lye to pH 13-14, clarifies with activated carbon and falls with dilute hydrochloric acid to pH 3.5. 27 g (911) of the title compound of mp 316-319 ° C. (from isopropanol) are obtained.
B2. 5-Trlfluormethoxv-1H-benzlmldazol-2-thlolB2. 5-trifluoromethoxv-1H-benzlmldazol-2-thlol
Analog Beispiel B1 erhält man durch Umsetzen von 4-Trifluormethoxy-1,2- phenylendiamin-dihydrochlorid (vgl. CA. 55, 23408d, 1961) mit Kalium- O-ethyldithiocarbonat und Natronlauge in Ethanol in 75% Ausbeute die Titelverbindung vom Schmp. 305-307°C (Zersetzung, aus Toluol).Analogously to Example B1, the title compound of mp 305 is obtained in 75% yield by reacting 4-trifluoromethoxy-1,2-phenylenediamine dihydrochloride (cf. CA. 55, 23408d, 1961) with potassium O-ethyldithiocarbonate and sodium hydroxide solution in ethanol -307 ° C (decomposed from toluene).
B3. 5-Difluormethoκv-1H-benzimldazol-2-thlolB3. 5-difluoromethoκv-1H-benzimldazol-2-thlol
a) 11,8 g N-(4-Difluormethoxyphenyl)-acetamld [L.M. Jagupol'skii et al., J.General Chemistry (USSR) 21, 190 (1969)] werden in 200 ml Dichlormethan mit 12,1 ml 100%iger Salpetersäure 1,5 h bei Raumtemperatur gerührt. Analog Beispiel B1b erhält man 13,3 g (92%) N-[(4-Difluor- methoxy-2-nitro)phenyl]-acetamid (Schmp. 71-73°C).a) 11.8 g of N- (4-difluoromethoxyphenyl) acetamide [L.M. Jagupol'skii et al., J. General Chemistry (USSR) 21, 190 (1969)] are stirred in 200 ml dichloromethane with 12.1 ml 100% nitric acid at room temperature for 1.5 h. Analogously to Example B1b, 13.3 g (92%) of N - [(4-difluoromethoxy-2-nitro) phenyl] acetamide (mp. 71-73 ° C.) are obtained.
b) Analog Beispiel Blc erhält man daraus in 96%iger Ausbeute 4-Difluor- methoxy-2-nitroanilin (Schmp. 68-70°C).b) Analogously to Example B1, 4-difluoromethoxy-2-nitroaniline (mp. 68-70 ° C.) is obtained therefrom in a 96% yield.
c) Analog Beispiel Bid erhält man in 94% Ausbeute 4-Difluormethoxy-1,2- phenylendiamin-dihydrochlorid.c) Analogous to Bid, 4-difluoromethoxy-1,2-phenylenediamine dihydrochloride is obtained in 94% yield.
d) Analog Beispiel B1e erhält man in 78% Ausbeute die Titelverbindung vom Schmp. 250-252°C (aus Isopropanol).d) Analogously to Example B1e, the title compound of mp 250-252 ° C. (from isopropanol) is obtained in 78% yield.
B4. 5-Difluormethoxy-6-methoxy-1H-benzimidazol-2-thlolB4. 5-difluoromethoxy-6-methoxy-1H-benzimidazole-2-thlol
a) In eine Lösung von 55,5 g Guajacol und 130 g Natriumhydroxid in 300 ml Wasser und 300 ml Dioxan werden bei 60°C ca. 58 g Chlordlfluormethan eingeleitet. Man filtriert die Mischung bei 10°C, trennt die organische Schicht ab, trocknet mit wasserfreiem Kaliumcarbonat und destilliert. Man erhält 56 g (73%) 1-Difluormethoxy-2-methoxybenzol vom Siedepunkt 75-76°C/0,9kPa.a) About 58 g of chlorodluoromethane are introduced into a solution of 55.5 g of guaiacol and 130 g of sodium hydroxide in 300 ml of water and 300 ml of dioxane at 60 ° C. The mixture is filtered at 10 ° C., the organic layer is separated off, dried with anhydrous potassium carbonate and distilled. 56 g (73%) of 1-difluoromethoxy-2-methoxybenzene with a boiling point of 75-76 ° C./0.9 kPa are obtained.
b) Zu einer Lösung von 47 g voranstehender Verbindung in 230 ml Di chlormethan wird bei 0-5°C eine Lösung von 33,8 ml 100%iger Salpetersäure in 90 ml Dichlormethan getropft, nach 30 Min. mit 250 ml Eiswasser versetzt und mit Kaliumhydrogancarbonat neutralisiert. Die getrocknete organische Phase wird im Vakuum eingeengt und der Rückstand aus Cyclohaxan umkristallisiert. Man arhält 53 g (90t) 1-Difluormethoxy-2- methoxy-5-nitrobenzol (Schmp. 48-49°C). Dieses wird analog Beispiel B1a hydriert und acetyliert. Man arhält in 90t Ausbeute N-(3-Difluor- methoxy-4-methoxyphenyl)acetamid (Schmp. 129-130°C).b) To a solution of 47 g of the above compound in 230 ml of Di chloromethane, a solution of 33.8 ml of 100% nitric acid in 90 ml of dichloromethane is added dropwise at 0-5 ° C., after 30 minutes, 250 ml of ice water are added and the mixture is neutralized with potassium hydrocarbonate. The dried organic phase is concentrated in vacuo and the residue is recrystallized from cyclohaxane. 53 g (90 t) of 1-difluoromethoxy-2-methoxy-5-nitrobenzene are obtained (mp. 48-49 ° C.). This is hydrogenated and acetylated analogously to Example B1a. N- (3-difluoromethoxy-4-methoxyphenyl) acetamide (mp. 129-130 ° C.) is obtained in a 90t yield.
c) 46 g voranstehender Verbindung werden mit 33 ml lOOtlger Salpetersäure in Dichlormethan analog voranstehender Vorschrift nitriert. Man erhält in 99t Ausbeute N-(5-Difluormethoxy-4-methoxy-2-nitrophenyl)- acetamid (Schmp. 116-117°C).c) 46 g of the above compound are nitrated with 33 ml of 100% nitric acid in dichloromethane analogously to the above regulation. N- (5-difluoromethoxy-4-methoxy-2-nitrophenyl) acetamide (mp. 116-117 ° C.) is obtained in a yield of 99t.
d) 54 g voranstehender Verbindung werden in 810 ml Methanol 1 h mitd) 54 g of the above compound are mixed in 810 ml of methanol for 1 h
44,8 ml 30tiger methanolischer Natriummethylatlösung bei Raumtemperatur gerührt. Man engt im Vakuum ein, versetzt mit Eiswasser und Eisessig bis pH 8 und erhält in 99% Ausbeute 5-Difluormethoxy-4-methoxy-2-nitro- anilln (Schmp. 144-145°C).44.8 ml of 30 tiger methanolic sodium methylate solution stirred at room temperature. The mixture is concentrated in vacuo, mixed with ice water and glacial acetic acid to pH 8 and 5-difluoromethoxy-4-methoxy-2-nitroanilene is obtained in 99% yield (mp. 144-145 ° C.).
e) 25 g voranstehender Verbindung werden in 300 ml -Methanol an 1,25 g 10%iger Palladiumkohle entsprechend Beispiel B1d hydriert. Man erhält 26 g (88%) 3-Difluormethoxy-4-methoxy-1,2-phenylendiamindihydrochlorid vom Schmp. 218-220°C (Zersetzung).e) 25 g of the above compound are hydrogenated in 300 ml of methanol over 1.25 g of 10% palladium carbon in accordance with Example B1d. 26 g (88%) of 3-difluoromethoxy-4-methoxy-1,2-phenylenediamine dihydrochloride with a melting point of 218-220 ° C. (decomposition) are obtained.
f) 25 g voranstehender Verbindung werden mit 19 g Kalium-0-ethyldithio- carbonat entsprechend Beispiel Bie umgesetzt. Man erhält 20 g (89%) der Titelverbindung vom Schmp. 280-282°C (Zersetzung; aus Isopropanol).f) 25 g of the above compound are reacted with 19 g of potassium 0-ethyldithiocarbonate according to Example Bie. 20 g (89%) of the title compound of mp 280-282 ° C. (decomposition; from isopropanol) are obtained.
B5. 2.2-Dlfluor-5H-[1,3]-dloxolo[4,5-f]benzlmldazol-6-thiolB5. 2,2-Difluoro-5H- [1,3] dloxolo [4,5-f] benzlmldazole-6-thiol
a) Man hydriert 30 g 4-Amino-2,2-difluor-5-nitro-1,3-benzodioxol in 300 ml Methanol an 0,5 g 10%iger Palladiumkohle in einer Umlaufhydrie- rungsapparatur bei Atmosphärendruck und Raumtemperatur, versetzt mit 2,5 Äquivalenten methanolischer Chlorwasserstofflösung, filtriert, engt die Lösung im Vakuum ein, versetzt mit Isopropanol und Ether und erhält 35 g (97 %) 2,2-Difluor-1,3-benzodioxol-4,5-diamin-dihydrochlorid vom Schmp. 232-233°C (Zersetzung). b) Man versetzt 30 g voranstehender Verbindung in 300 ml Ethanol mit 24 g Kalium-0-ethyldithiocarbonat (umkristallisiert aus Isopropanol) und 9,2 g Natriumhydroxid in 55 ml Wasser und erhitzt 15 h unter Rück- fluß zum Sieden. Man gie8t auf 1,5 1 Wasser, stellt mit Natronlauge auf pH 14, klärt mit Aktivkohle, fällt mit konzentrierter Salzsäura in der Wärme und saugt den Niederschlag in dar Kälte ab. Man arhält 24 g (91 t) der Titelverbindung vom Schmp. 365-370°C (Zersetzung).a) 30 g of 4-amino-2,2-difluoro-5-nitro-1,3-benzodioxole are hydrogenated in 300 ml of methanol over 0.5 g of 10% palladium-carbon in a circulating hydrogenation apparatus at atmospheric pressure and room temperature, mixed with 2.5 equivalents of methanolic hydrogen chloride solution, filtered, the solution is concentrated in vacuo, mixed with isopropanol and ether and receives 35 g (97%) of 2,2-difluoro-1,3-benzodioxol-4,5-diamine dihydrochloride of mp . 232-233 ° C (decomposition). b) 24 g of potassium 0-ethyldithiocarbonate (recrystallized from isopropanol) and 9.2 g of sodium hydroxide in 55 ml of water are added to 30 g of the above compound in 300 ml of ethanol and the mixture is heated to boiling under reflux for 15 h. It is poured onto 1.5 l of water, adjusted to pH 14 with sodium hydroxide solution, clarified with activated carbon, precipitated with concentrated hydrochloric acid in the heat and the precipitate is suctioned off in the cold. 24 g (91 t) of the title compound of mp 365-370 ° C. (decomposition) are obtained.
66. 6.6.7-Trlfluor-6.7-dlhvdro-1H-[1.4]-dioxlnor2.3-f]benzlmldazol-2- thiol.66. 6.6.7-Trlfluoro-6.7-dlhvdro-1H- [1.4] -dioxlnor2.3-f] benzlmldazol-2-thiol.
a) Zu 50 g 2 , 2,3-Trifluor-2,3-dihydro-1, 4-benzodioxin wird bei 5°C in 1 h eine Mischung von 39,5 ml 69%iger Salpetersäure und 46 ml 97%igera) A mixture of 39.5 ml of 69% nitric acid and 46 ml of 97% strength is added to 50 g of 2, 2,3-trifluoro-2,3-dihydro-1,4-benzodioxin at 5 ° C. in 1 hour
Schwefelsäure getropft. Han rührt 1 h bei 10°C, 1 h bei 20°C und 5 Min. bei 40°C und gießt auf 200 g Eis, extrahiert mit Dichlormethan, wäscht mit Wasser, trocknet mit Magnesiumsulfat und destilliert im Vakuum. Man erhält 58 g (94 t) einer Mischung von 2,2,3-Trifluor-2,3-dihydro-6- nitro-(und 7-nitro)-1,4-benzodioxin vom Sdp. 68,5°C (0,15 mbar) und 1,5080. Ein Gaschromatogramm mit einer 10 m Fused Silica SäuleDropped sulfuric acid. Han stirred for 1 h at 10 ° C, 1 h at 20 ° C and 5 min. At 40 ° C and poured onto 200 g of ice, extracted with dichloromethane, washed with water, dried with magnesium sulfate and distilled in vacuo. 58 g (94 t) of a mixture of 2,2,3-trifluoro-2,3-dihydro-6-nitro- (and 7-nitro) -1,4-benzodioxine with a melting point of 68.5 ° C. ( 0.15 mbar) and 1.5080. A gas chromatogram with a 10 m fused silica column
(Fa. Chrompack) zeigt zwei Peaks im Verhältnis 2:3.(Chrompack) shows two peaks in a ratio of 2: 3.
b) Man hydriert 35 g des Isomerengemisches in 400 ml Ethanol an 3 g 10%iger Palladiumkohle bei Atmosphärendruck und 20-30°C in einer Umlaufhydrierungsapparatur, filtriert und engt im Vakuum ein. Man erhält 30,5 g (100 %) einer flüssigen Mischung von 6-Amino-(und 7-Amlno)-b) 35 g of the isomer mixture are hydrogenated in 400 ml of ethanol on 3 g of 10% palladium-carbon at atmospheric pressure and 20-30 ° C. in a circulating hydrogenation apparatus, filtered and concentrated in vacuo. 30.5 g (100%) of a liquid mixture of 6-amino- (and 7-amlno) are obtained.
2,2,3-trifluor-2,3-dihydro-1,4-benzodioxin.2,2,3-trifluoro-2,3-dihydro-1,4-benzodioxin.
c) Zu 28 g der voranstehenden Isomerenmischung tropft man bei 20-30°C eine Mischung aus 15,3 g Essigsäureanhydrid und 15 ml Eisessig, rührt 30 Min. bei 30°C, setzt 1 ml Wasser zu, rührt 30 Min. bei 30°C und destilliert das Lösungsmittel im Vakuum ab. Durch Umkristallisation aus Toluol erhalt man 19 g einer Fraktion des Gemisches der isomeren Acetaminoderivate vom Schmp. 128-133°C.c) A mixture of 15.3 g of acetic anhydride and 15 ml of glacial acetic acid is added dropwise to 28 g of the above isomer mixture at 20-30 ° C., the mixture is stirred at 30 ° C. for 30 minutes, 1 ml of water is added and the mixture is stirred at 30 for 30 minutes ° C and distilled off the solvent in vacuo. Recrystallization from toluene gives 19 g of a fraction of the mixture of the isomeric acetamino derivatives, mp. 128-133 ° C.
d) Zu 17 g des Isomerengemisches der Acetamlnoderivate, suspendiert in 200 ml Dichlormethan, tropft man bei -6° bis -8°C 14 ml 100%ige Salpe tersäure, galöst in 60 ml Dichlormethan, rührt 2 h bei 0°C und dann Ober Nacht bei Raumtemperatur. Man gießt auf 110 g Eis, trennt die organische Phase ab, wäscht mit Wasser und engt im Vakuum ein. Der Rückstand (19,8 g) wird aus 20 ml Ethanol umkristallisiert; Man arhält 15,5 g einer Mischung von 6-Acetamino-2,2,3-trifluor-2,3-dlhydro-7- nitro-1, 4-benzodioxln und 7-Acetamino-2,2,3-trifluor-2,3-dihydro-6- nitro-1,4-benzodioxin.d) To 17 g of the isomer mixture of the acetamlnoderivate, suspended in 200 ml dichloromethane, 14 ml of 100% salpe are added dropwise at -6 ° to -8 ° C tersäure, galöst in 60 ml dichloromethane, stirred for 2 h at 0 ° C and then overnight at room temperature. It is poured onto 110 g of ice, the organic phase is separated off, washed with water and concentrated in vacuo. The residue (19.8 g) is recrystallized from 20 ml of ethanol; 15.5 g of a mixture of 6-acetamino-2,2,3-trifluoro-2,3-dlhydro-7-nitro-1,4-benzodioxln and 7-acetamino-2,2,3-trifluoro-2 are obtained , 3-dihydro-6-nitro-1,4-benzodioxin.
a) Man suspendiert 14,5 g des voranstehenden Produktgemisches in 80 ml Methanol und tropft unter Erwärmung auf 30°C 30 ml 5m Natronlauge zu. Man rührt noch 0,5 h bei Raumtemperatur, gie8t auf 200 g Eis und erhält 11,7 g einer Mischung von 6-Amino-2,2,3-trlfluor-2,3-dihydro-7-nitro- 1 ,4-benzodioxin und 7-Amino-2,2,3-trifluor-2,3-dihydro-6-nitro-1,4- benzodioxin. Eine Probe wird an einer Kieselgelsäule mit Cyclohe- xan/Essigsäureethylester (4:1) in zwei reine Isomeren mit den Schmelzpunkten 110, 5-111, 5°C und 120-121°C getrennt, deren NMR-Spektren an einem 60 MHz-Gerät in Deuterochloroform praktisch identisch sind.a) 14.5 g of the above product mixture are suspended in 80 ml of methanol and 30 ml of 5M sodium hydroxide solution are added dropwise while heating to 30 ° C. The mixture is stirred for a further 0.5 h at room temperature, poured onto 200 g of ice and 11.7 g of a mixture of 6-amino-2,2,3-trlfluoro-2,3-dihydro-7-nitro-1,4-are obtained. benzodioxin and 7-amino-2,2,3-trifluoro-2,3-dihydro-6-nitro-1,4-benzodioxin. A sample is separated on a silica gel column with cyclohexane / ethyl acetate (4: 1) into two pure isomers with melting points 110, 5-111, 5 ° C and 120-121 ° C, whose NMR spectra on a 60 MHz Device in deuterochloroform are practically identical.
f) 10,9 g des voranstehenden Isomerengemisches werden in 300 ml Methanol bei Raumtemperatur und AtmosphSrendruck an 1 g lOtiger Palladiumkohle in 2,5 h hydriert. Man setzt 30 ml 4 m Chlorwasserstoff in Methanol zu, filtriert, engt im Vakuum ein und verrührt mit 100 ml Ether. Man erhält 12,6 g (98 %) 2,2,3-Trifluor-2,3-dihydro-1,4-benzodioxin- 6,7-diamin-dihydrochlorid (Schmp. >250°C).f) 10.9 g of the above isomer mixture are hydrogenated in 300 ml of methanol at room temperature and atmospheric pressure over 1 g of soldered palladium-carbon in 2.5 h. 30 ml of 4 M hydrogen chloride in methanol are added, the mixture is filtered, concentrated in vacuo and stirred with 100 ml of ether. 12.6 g (98%) of 2,2,3-trifluoro-2,3-dihydro-1,4-benzodioxin-6,7-diamine dihydrochloride (mp.> 250 ° C.) are obtained.
g) 12 g voranstehender Verbindung und 8,5 g Kalium-0-ethyldithiocarbo- nat (umkristallisiert aus Isopropanol) werden in 120 ml Ethanol mit 20,5 ml 4 m wäßriger Kaliumhydroxidlösung versetzt und 17 h unter Rückfluß zum Sieden erhitzt. Man gießt auf 300 g Eis, stellt mit Kaliumhy- droxidlösung auf pH 12-13, klärt mit Aktivkohle und fällt mit konzentrierter Salzsäure. Nach erneuter Fällung mit Säure aus alkalischer wäßrig-alkoholischer Lösung erhält man 10 g (93 %) der Titelverbindung vom Schmp. 309-310°C (Zersetzung). Gewerbllche Anwendbarkeitg) 12 g of the above compound and 8.5 g of potassium 0-ethyldithiocarbonate (recrystallized from isopropanol) are mixed in 120 ml of ethanol with 20.5 ml of 4 M aqueous potassium hydroxide solution and heated to boiling under reflux for 17 h. It is poured onto 300 g of ice, adjusted to pH 12-13 with potassium hydroxide solution, clarified with activated carbon and precipitated with concentrated hydrochloric acid. After reprecipitation with acid from an alkaline aqueous-alcoholic solution, 10 g (93%) of the title compound of mp 309-310 ° C. (decomposition) are obtained. Commercial applicability
Die erfindungsgemäßen Verbindungen der Formel I und ihre Salze besitzen wertvolle pharmakologische Eigenschaften, die sie gewerblich verwertbar machen. Sie hemmen deutlich die Magansäuresekretion von Warmblütern und weisen darüberhinaus eine ausgezeichnete Magen- und Darmschutzwirkung bei Warmblütern auf. Diese Magen- und Darmschutzwirkung wird teilweise bereits bei der Verabreichung von Dosen beobachtet, die unterhalb der säuresekretionshemmenden Dosen liegen. Darüberhinaus zeichnen sich die erfindungsgemäßen Verbindungen durch das Fehlen wesentlicher Nebenwirkungen und eine große therapeutische Breite aus. Ein weiterer erfindungswesentlicher Aspekt besteht darin, daß die Verbindungen der Formel I im jeweils erwünschten pH-Bereich eine hohe chemische Stabilität und ein signifikantes Wirkungsmaximum aufweisen.The compounds of the formula I according to the invention and their salts have valuable pharmacological properties which make them commercially usable. They clearly inhibit the magnesic acid secretion of warm-blooded animals and also have an excellent gastric and intestinal protective effect in warm-blooded animals. This gastric and intestinal protective effect is sometimes already observed when doses are administered which are below the acid secretion-inhibiting doses. In addition, the compounds according to the invention are distinguished by the absence of significant side effects and a large therapeutic breadth. Another aspect essential to the invention is that the compounds of the formula I have high chemical stability and a significant maximum activity in the pH range desired in each case.
Unter "Magen- und Darmschutz" wird in diesem Zusammenhang die Verhütung und Behandlung gastrointestinaler Krankheiten, insbesondere gastrointestinaler entzündlicher Krankheiten und Läsionen (wie z.B. Ulcus ventriculi, Ulcus duodeni, Gastritits, hyperazider oder medikamentös bedingter Reizmagen) verstanden, die beispielsweise durch Mikroorganismen, Bakterientoxine, Medikamente (z.B. bestimmte Antiphlogistika und Antirheumatika), Chemikalien (z.B. Ethanol), Magensäure oder Streßsituationen verursacht werden können.In this context, "gastric and intestinal protection" means the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach), which are caused, for example, by microorganisms, bacterial toxins, Medications (e.g. certain anti-inflammatory drugs and anti-rheumatic drugs), chemicals (e.g. ethanol), stomach acid or stressful situations can be caused.
In ihren ausgezeichneten Eigenschaften erweisen sich die erfindungsgemäßen Verbindungen überraschenderweise den aus dem Stand der Technik bekannten Verbindungen deutlich überlegen. Aufgrund dieser Eigenschaften sind die erfindungsgemäßen Verbindungen und ihre pharmakologisch verträglichen Salze für den Einsatz in der Human- und Veterinärmedizin hervorragend geeignet, wobei sie insbesondere zur Behandlung und Prophylaxe von Krankheiten des Magens und Darms und solcher Krankheiten, die auf einer überhöhten Magensäuresekretion beruhen, verwendet werden. Die hohe Lagerstabilität der erfindungsgemä8en Verbindungen ermöglicht dabei ihren problemlosen Einsatz in pharmazeutischen Zubereitungen.In their excellent properties, the compounds according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art. Because of these properties, the compounds according to the invention and their pharmacologically tolerated salts are outstandingly suitable for use in human and veterinary medicine, and are used in particular for the treatment and prophylaxis of diseases of the stomach and intestines and of diseases which are based on excessive gastric acid secretion . The high storage stability of the compounds according to the invention enables their problem-free use in pharmaceutical preparations.
Ein weiterer Gegenstand der Erfindung sind die erfindungsgemäßen Ver bindungen zur Anwendung bei der Behandlung und Prophylaxe der vorstehend genannten Krankheiten.The invention also relates to the invention bindings for use in the treatment and prophylaxis of the aforementioned diseases.
Ebenso umfaßt die Erfindung die Verwendung dar erfindungsgemäBen Verblndungen bei der Herstellung von Arzneimitteln, die zur Behandlung und Prophylaxe dar vorstehend genannten Krankheiten eingesetzt werden.The invention also includes the use of the blindings according to the invention in the manufacture of medicaments which are used for the treatment and prophylaxis of the abovementioned diseases.
Ein weiterer Gegenstand der Erfindung sind Arzneimittel, die ein oder mehrere erfindungsgemäße Verbindungen der Formel I und/oder ihre pharmakologisch verträglichen Salze enthalten.The invention further relates to medicaments which contain one or more compounds of the formula I according to the invention and / or their pharmacologically tolerable salts.
Die Arzneimittel werden nach an sich bekannten, dem Fachmann geläufigen Verfahren hergestellt. Als Arzneimittel werden die erflndungsgemäßen pharmakologisch wirksamen Verbindungen (= Wirkstoffe) entweder als solehe, oder vorzugsweise in Kombination mit geeigneten pharmazeutischen Hilfsstoffen in Form von Tabletten, Dragees, Kapseln, Suppositorien, Pflastern (z.B. als TTS), Emulsionen, Suspensionen oder Lösungen eingesetzt, wobei der Wirkstoffgehalt vorteilhafterweise zwischen 0,1 und 95 % beträgt.The pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art. The pharmacologically active compounds (= active ingredients) according to the invention are used as medicinal products either as such or preferably in combination with suitable pharmaceutical auxiliaries in the form of tablets, dragées, capsules, suppositories, plasters (for example as TTS), emulsions, suspensions or solutions, where the active ingredient content is advantageously between 0.1 and 95%.
Welche Hilfsstoffe für die gewünschten Arzneimittelformulierungen geeignet sind, ist dem Fachmann aufgrund seines Fachwissens geläufig. Neben Lösemitteln, Gelbildnern, Suppositoriengrundlagen, Tabletten- Hilfsstoffen und anderen Wirkstoffträgern können beispielsweise Antioxidantien, Dispergiermittel, Emulgatoren, Entschäumer, Geschmacks- korrigentien, Konservierungsmittel, Lösungsvermittler, Farbstoffe oder insbesondere Permeationspromotoren und Komplexbildner (z.B. Cyclo- dextrine) verwendet werden.The person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gel formers, suppository bases, tablet excipients and other active substance carriers, for example antioxidants, dispersants, emulsifiers, defoamers, taste correctives, preservatives, solubilizers, colorants or in particular permeation promoters and complexing agents (e.g. cyclodextrins) can be used.
Die Wirkstoffe können oral, parenteral oder percutan appliziert werden.The active ingredients can be administered orally, parenterally or percutaneously.
Im allgemeinen hat es sich in der Humanmedizin als vorteilhaft erwiesen, den oder die Wirkstoffe bei oraler Gabe in einer Tagesdosis von etwa 0,05 bis etwa 50, vorzugsweise 0,25 bis 20, insbesondere 0,5 bis 10 mg/kg Körpergewicht, gegebenenfalls in Form mehrerer, vorzugsweise 1 bis 4 Einzelgaben zur Erzielung des gewünschten Ergebnisses zu verabreichen. Bei einer parenteralen Behandlung können ähnliche bzw. (insbesondere bei der intravenösen Verabreichung der Wirkstoffe) in der Re gel niedrigere Dosierungen zur Anwendung kommen. Die Festlegung der jeweils erforderlichen optimalen Dosierung und Applikationsart der Wirkstoffe kann durch jaden Fachmann aufgrund seines Fachwissens leicht erfolgen.In general, it has proven advantageous in human medicine to optionally give the active ingredient (s) when administered orally in a daily dose of about 0.05 to about 50, preferably 0.25 to 20, in particular 0.5 to 10 mg / kg body weight in the form of several, preferably 1 to 4 individual doses to achieve the desired result. In the case of parenteral treatment, similar or (especially in the case of intravenous administration of the active compounds) in the gel lower doses are used. The optimum dosage and type of application of the active ingredients required in each case can easily be determined by a specialist based on his specialist knowledge.
Sollen die erfindungsgemäßen Verbindungen und/oder ihre Salze zur Behandlung der oben genannten Krankheiten eingesetzt werden, so können die pharmazeutischen Zubereitungen auch einen oder mehrere pharmakologisch aktive Bestandteile anderer Arzneimittelgruppen, wie Antacida, beispielsweise Aluminiumhydroxid, Magnesiumaluminat; Tranquillizer, wie Benzodiazepine, beispielsweise Dlazepam; Spasmolytika, wie z.B. Bietamiverin, Camylofin; Anticholinergica, wie z.B. Oxyphencyclimin, Phen- carbamid; Lokalanaesthetika, wie z.B. Tetracain, Procain-, gegebenenfalls auch Fermente, Vitamine oder Aminosäuren enthalten.If the compounds according to the invention and / or their salts are to be used for the treatment of the abovementioned diseases, the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other groups of medicaments, such as antacids, for example aluminum hydroxide, magnesium aluminate; Tranquillizers, such as benzodiazepines, for example dlazepam; Antispasmodics, e.g. Bietamiverin, Camylofin; Anticholinergics such as Oxyphencyclimine, phencarbamide; Local anesthetics, e.g. Tetracaine, procaine, and possibly also ferment, vitamins or amino acids.
Hervorzuheben ist in diesem Zusammenhang insbesondere die Kombination der erfindungsgemä8en Verbindungen mit anderen, die Säuresekretion hemmenden Pharmaka, wie beispielsweise H2-Blockern (z.B. Cimetidin, Ranltidin), ferner mit sogenannten peripheren Anticholinergika (z.B. Pirenzepin, Telenzepin, Zolenzepin) sowie mit Gastrin-Antagonisten, mit dem Ziel, die Hauptwirkung in additivem oder überadditivem Sinn zu verstärken und/oder die Nebenwirkungen zu eliminieren oder zu verringern. In this context, the combination of the compounds according to the invention with other drugs which inhibit acid secretion, such as H 2 blockers (for example cimetidine, ranltidine), with so-called peripheral anticholinergics (for example pirenzepin, telenzepin, zolenzepin) and with gastrin antagonists should be emphasized in particular , with the aim of strengthening the main effect in an additive or superadditive sense and / or eliminating or reducing the side effects.
Pharmakologiepharmacology
Die ausgezeichnete Maganschutzwirkung und die magensekretlonshemmendeThe excellent magan protective effect and the gastric secretion-inhibiting
Wirkung der erfindungsgemäßen Verbindungen Iäßt sich tierexperimentell mm Modell Shay-Ratte nachweisen. Die untersuchten erfindungsgemäßen Verbindungen sind wie folgt mit Nummern versehen worden:Effect of the compounds according to the invention can be demonstrated in animal experiments in the Shay rat model. The investigated compounds according to the invention have been numbered as follows:
Lfd. Nr. Name der VerbindungCurrent No. Name of the connection
6-[4-Dimethylaminopyridyl-(2)-methylsulfinyl]-2,2-difluor-5H- [1,3]-dioxolo[4,5-f]benzimidazol6- [4-Dimethylaminopyridyl- (2) methylsulfinyl] -2,2-difluoro-5H- [1,3] dioxolo [4,5-f] benzimidazole
2 5-Difluormethoxy-2-[3-methyl-4-morpholinopyridyl-(2)-methylsulfinyl]-1H-benzimidazol2 5-difluoromethoxy-2- [3-methyl-4-morpholinopyridyl- (2) -methylsulfinyl] -1H-benzimidazole
3 2,2-Dlfluor-6-[3-methyl-4-morpholinopyrldyl-(2)-methyl- sulfinyl]-5H-[1,3]-dioxolo[4,5-f]benzimidazol3 2,2-Difluoro-6- [3-methyl-4-morpholinopyrldyl- (2) -methylsulfinyl] -5H- [1,3] dioxolo [4,5-f] benzimidazole
Der Einfluß der untersuchten Verbindungen auf die durch PylorusligaturThe influence of the examined compounds on the pylorus ligation
(4h; sog. Shay-Ratte) und orale Gabe von 100 mg/kg Acetylsalicylsäure ausgelöste Magenläslonsbildung sowie die Magensekretion (HCl) während 4 h bei der Ratte, ist in der folgenden Tabelle dargestellt. Magenschutzwirkung und Magensekretionshemmung(4h; so-called Shay rat) and oral administration of 100 mg / kg acetylsalicylic acid triggered gastric lesion formation as well as gastric secretion (HCl) for 4 h in the rat is shown in the following table. Gastric protective effect and gastric secretion inhibition
+ ) ED25 bzw. ED50 Dosis, die den Läsionsindex bzw. die HCl-Sekretion (4h) des Rattenmagens bei der behandelten Gruppe gegenüber der Kontrollgruppe um 25 bzw. 50 % mindert.+) ED25 or ED50 dose that reduces the lesion index or the HCl secretion (4h) of the rat stomach in the treated group compared to the control group by 25 or 50%.
+ + ) nach Gabe der antiulcerösen ED50+ +) after administration of the antiulcerous ED50
Die Prüfung der antiulcerogenen Wirkung erfolgte nach der Methode der sogenannten Shay-Ratte:The antiulcerogenic effect was tested using the so-called Shay rat method:
Die Ulcusprovokation erfolgt bei 24 Stunden nüchtern gehaltenen Ratten (weiblich, 180-200 g, 4 Tiere je Käfig auf hohem Gitterrost) durchThe ulcer provocation takes place in 24 hours fasted rats (female, 180-200 g, 4 animals per cage on a high grating)
Pylorusligatur (unter Diethylethernarkose) und orale Applikation von 100 mg/10 ml/kg Acetylsalicylsäure. Die zu prüfenden Substanzen werden oral (10 ml/kg) eine Stunde vor der Pylorusligatur verabreicht. Der Wundverschluß wird mittels Michelklammern vorgenommen. 4 Stunden danach erfolgt die Tötung der Tiere im Etherrausch durch Atlas-Dislokation und die Resektion des Magens. Der Magen wird längs eröffnet und auf einer Korkplatte fixiert, nachdem zuvor die Menge des sezernierten Magensaftes (Volumen) und später sein HCl-Gehalt (Titration mit Natronlauge) bestimmt wurde; mit einem Stereomikroskop werden bei 10-facher Vergrößerung Anzahl und Größe (=Durchmesser ) vorhandener Ulcera ermittelt. Das Produkt aus Schweregrad (gemäß nachfolgender Punkteskala) und Anzahl der Ulcera dient als individueller Läsionsindex. Punkteskala: keine Ulcera 0Pylorus ligation (under diethyl ether anesthesia) and oral application of 100 mg / 10 ml / kg acetylsalicylic acid. The substances to be tested are administered orally (10 ml / kg) one hour before the pylorus ligation. The wound is closed using Michel clips. 4 hours later, the animals were killed in ether rush by atlas dislocation and resection of the stomach. The stomach is opened lengthways and fixed on a cork plate after the amount of gastric juice secreted (volume) and later its HCl content (titration with sodium hydroxide solution) has been determined; with a stereomicroscope, the number and size (= diameter) of existing ulcers are determined at 10x magnification. The product of the severity (according to the following scale of points) and the number of ulcers serves as an individual lesion index. Score scale: no ulcers 0
Ulcusdurchmesser 0,1 - 1,4 mm 1Ulcer diameter 0.1 - 1.4 mm 1
1,5 - 2,4 mm 21.5 - 2.4 mm 2
2,5 - 3,4 mm 32.5 - 3.4 mm 3
3,5 - 4,4 mm 43.5 - 4.4 mm 4
4,5 - 5,4 mm 54.5 - 5.4 mm 5
> 5,5 mm 6> 5.5 mm 6
Als Maß für den antiulcerogenen Effekt dient die Minderung des mittleren Läsionsindex jeder behandelten Gruppe gegenüber dem derThe measure of the antiulcerogenic effect is the reduction in the mean lesion index of each treated group compared to that of the
Kontrollgruppe (=100%). Die ED25 bzw. ED50 bezeichnen diejenigen Dosen, die den mittleren Läsionsindex bzw. die HCl-Sekretion gegenüber der Kontrolle um 25% bzw. 50% mindern.Control group (= 100%). The ED25 and ED50 denote those doses that reduce the mean lesion index or HCl secretion by 25% and 50% compared to the control.
ToxlzitätToxicity
Die LD50 aller geprüften Verbindungen liegt oberhalb von 1000 mg/kg [p.o.] bei der Maus. The LD50 of all tested compounds is above 1000 mg / kg [p.o.] in the mouse.

Claims

Patentansprüche Claims
Aminoverbindungen der Formal IAmino compounds of formal I
worinwherein
R1, R2, R3 und R4 an beliebigen Positionen im Benzoteil des Benzimidazols stehen können und worinR1, R2, R3 and R4 can be at any position in the benzo part of the benzimidazole and where
R1 Wasserstoff oder C1-C6-Alkyl bedeutet, R2 Wasserstoff, Cyan, Nitro, Halogen, Trifluormethyl, C1-C6-Alkyl, C1-C6-Alkoxy, C1-C4-Alkoxy-C1-C4-alkyl, C1-C2-Alkylendioxy-C1-C4- alkyl, Hydroxy-C1-C4-alkyl, Cyan-C1-C4-alkoxy, C1-C4-Alkoxy-C1-C4- alkoxy, C1-C6-Alkylcarbonyl, C1-C4-Alkoxycarbonyl, Phenyl, Phenoxy, Phenoxy-C1-C4-alkyl, Phenoxy-C1-C4-alkoxy, Phen-C1-C4- alkyl, Phen-C1-C4-alkoxy oder Benzoyl bedeutet,R1 is hydrogen or C 1 -C 6 alkyl, R2 is hydrogen, cyano, nitro, halogen, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 4 alkoxy-C 1 - C 4 -alkyl, C 1 -C 2 -alkylenedioxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, cyano-C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 alkoxy, C 1 -C 6 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, phenyl, phenoxy, phenoxy-C 1 -C 4 alkyl, phenoxy-C 1 -C 4 alkoxy, phen-C 1 -C 4 alkyl, phen-C 1 -C 4 alkoxy or benzoyl,
R3 Wasserstoff, C1-C6-Alkyl, C1-C6-Alkoxy , ganz oder überwiegend durch Fluor substituiertes C1-C4-Alkoxy, Chlordifluormethoxy, 2-Chlor-1,1,2-trifluorethoxy oder gemeinsam mit R4 ganz oder teilweise durch Fluor substituiertes C1-C2-Alkylendioxy oder Chlortrifluorethylendloxy bedeutet,R3 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, completely or predominantly substituted by fluorine-substituted C 1 -C 4 -alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R4 C 1 -C 2 -alkylenedioxy or chlorotrifluoroethylenedloxy which is wholly or partly substituted by fluorine,
R4 ganz oder überwiegend durch Fluor substituiertes C1-C4-Alkoxy,R4 completely or predominantly fluorine-substituted C 1 -C 4 alkoxy,
Chlordlfluormethoxy, 2-Chlor-1,1,2-trifluorethoxy oder gemeinsam mit R3 ganz oder teilweise durch Fluor substituiertes C1-C2-Alky- lendioxy oder Chlortrifluorethylendloxy bedeutet, R5 Wasserstoff oder eine unter physiologischen Bedingungen leicht abspaltbare Gruppe bedeutet,Chlorodlfluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R3 completely or partly substituted by fluorine substituted C 1 -C 2 -alkylenedioxy or chlorotrifluoroethylene dloxy, R5 means hydrogen or a group which can easily be split off under physiological conditions,
R6 Wasserstoff oder C1-C4-Alkyl bedeutet, R7 Wasserstoff, C1-C4-Alkyl, C1-C4-Alkoxy oder gemeinsam mit R8a C2-C3-Alkylen bedeutet,R6 represents hydrogen or C 1 -C 4 alkyl, R7 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or together with R8a is C 2 -C 3 -alkylene,
R8a Wasserstoff, C1-C4-Alkyl, C1-C4-Alkenyl, gemeinsam mit R7 C2-C3- Alkylen, gemeinsam mit R9 C2-C3-Alkylen oder gemeinsam mit RBb gegebenenfalls durch Sauerstoff unterbrochenes C4-C6-Alkylen bedeutet,R8a is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, together with R7 C 2 -C 3 alkylene, together with R9 C 2 -C 3 alkylene or together with RBb optionally C 4 interrupted by oxygen Means -C 6 alkylene,
RBb Wasserstoff, C1-C4-Alkyl, C1-C4-Alkenyl, C1-C4-Alkylcarbonyl oder gemeinsam mit R8a gegebenenfalls durch Sauerstoff unterbrochenes C4-C6-Alkylen bedeutet, R9 Wasserstoff, C1-C4-Alkyl, C1-C4-Alkoxy oder gemeinsam mit R8a C2-C3-Alkylen bedeutet,RBb is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkenyl, C 1 -C 4 -alkylcarbonyl or together with R8a C 4 -C 6 -alkylene optionally interrupted by oxygen, R9 is hydrogen, C 1 -C 4- alkyl, C 1 -C 4 -alkoxy or together with R8a is C 2 -C 3 -alkylene,
R10 Wasserstoff oder C1-C4-Alkyl bedeutet und n die Zahlen 0 der 1 darstellt, und die Salze dieser Verbindungen.R10 represents hydrogen or C 1 -C 4 alkyl and n represents the numbers 0 or 1 , and the salts of these compounds.
Verbindungen der Formel I nach Anspruch 1, worinCompounds of formula I according to claim 1, wherein
R1 Wasserstoff, Methyl oder Ethyl bedeutet,R1 is hydrogen, methyl or ethyl,
R2 Wasserstoff, Chlor, Fluor, Trifluormethyl, Methyl, Ethyl, Methoxy, Ethoxy, Acetyl, Methoxycarbonyl oder Ethoxycarbonyl bedeutet,R2 represents hydrogen, chlorine, fluorine, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, acetyl, methoxycarbonyl or ethoxycarbonyl,
R3 Wasserstoff, Methyl, Ethyl, Methoxy, Ethoxy, 1,1,2,2-Tetrafluor- ethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy, Difluormethoxy oder gemeinsam mit R4 Difluormethylendioxy, 1,1,2-Trifluorethylendioxy oder 1-Chlor-1,2,2-trlfluorethylendioxy bedeutet, R4 1,1,2,2-Tetrafluorethoxy, Trifluormethoxy, 2,2,2-Trifluorethoxy, Difluormethoxy oder gemeinsam mit R3 Difluormethylendloxy, 1,1,2- Trifluorethylendloxy oder 1 -Chlor- 1,2,R3 is hydrogen, methyl, ethyl, methoxy, ethoxy, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy or together with R4 difluoromethylene dioxy, 1,1,2-trifluoroethylene dioxy or 1- Chloro-1,2,2-trlfluoroethylenedioxy means, R4 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy or together with R3 difluoromethylenedloxy, 1,1,2-trifluoroethylenedloxy or 1-chlorine - 1.2,
2-trifluorethylendioxy bedeutet,2-trifluoroethylene dioxy means
R5 Wasserstoff bedeutet, R6 Wasserstoff, Methyl oder Ethyl bedeutet,R5 means hydrogen, R6 means hydrogen, methyl or ethyl,
R7 Wasserstoff, Methyl, Ethyl, Methoxy, Ethoxy oder gemeinsam mit R8a Ethylen oder Propylen bedeutet,R7 denotes hydrogen, methyl, ethyl, methoxy, ethoxy or together with R8a ethylene or propylene,
R8a Wasserstoff, Methyl, Ethyl, gemeinsam mit R7 Ethylen oderR8a is hydrogen, methyl, ethyl, together with R7 or ethylene
Propylen, gemeinsam mit R9 Ethylen oder Propylen oder gemeinsam mit R8b und dem Stickstoffatom, woran beide gebunden sind, Pyrrolidino, Piperidino oder Morpholino bedeutet,Propylene, together with R9 means ethylene or propylene or together with R8b and the nitrogen atom, to which both are bound, means pyrrolidino, piperidino or morpholino,
R8b Wasserstoff, Methyl, Ethyl, Acetyl oder gemeinsam mit R8a und dem Stickstoffatom, woran beide gebunden sind, Pyrrolidino, Piperidino oder Morpholino bedeutet, R9 Wasserstoff, Methyl, Ethyl, Methoxy, Ethoxy oder gemeinsam mit R8aR8b is hydrogen, methyl, ethyl, acetyl or together with R8a and the nitrogen atom, to which both are bound, pyrrolidino, piperidino or morpholino, R9 is hydrogen, methyl, ethyl, methoxy, ethoxy or together with R8a
Ethylen oder Propylen bedeutet, R10 Wasserstoff, Methyl oder Ethyl bedeutet und n die Zahlen 0 oder 1 darstellt, und die Salze dieser Verbindungen.Ethylene or propylene means R10 means hydrogen, methyl or ethyl and n represents the numbers 0 or 1, and the salts of these compounds.
3. Verbindungen nach Anspruch 2, worin R7 und R9 Wasserstoff bedeuten, und ihre Salze.3. Compounds according to claim 2, wherein R7 and R9 are hydrogen, and their salts.
4. Verbindungen nach Anspruch 2, worin R7 Methyl oder Ethyl bedeutet und R9 Wasserstoff bedeutet, und ihre Salze.4. Compounds according to claim 2, wherein R7 is methyl or ethyl and R9 is hydrogen, and their salts.
5. Verbindungen nach Anspruch 2 oder 3 oder 4, worin R6 und R10 Wasserstoff bedeuten, und ihre Salze.5. Compounds according to claim 2 or 3 or 4, wherein R6 and R10 are hydrogen, and their salts.
6. Verbindungen der Formel I nach Anspruch 1, worin R1 Wasserstoff bedeutet,6. Compounds of formula I according to claim 1, wherein R1 is hydrogen,
R2 Wasserstoff bedeutet, R3 Wasserstoff oder gemeinsam mit R4 Difluormethylendloxy bedeutet,R2 means hydrogen, R3 means hydrogen or together with R4 difluoromethyleneendloxy,
R4 1,1,2,2-Tetrafluorethoxy, Difluormethoxy oder gemeinsam mit R3 Difluormethylendloxy bedeutet,R4 denotes 1,1,2,2-tetrafluoroethoxy, difluoromethoxy or together with R3 difluoromethyleneendloxy,
R5 Wasserstoff bedeutet,R5 means hydrogen
R6 Wasserstoff bedeutet, R7 Waserstoff oder Methyl bedeutet,R6 means hydrogen, R7 means hydrogen or methyl,
R8a Methyl oder gemeinsam mit R8b und dem Stickstoffatom, woran beide gebunden sind, Pyrrolidino oder Morpholino bedeutet,R8a is methyl or together with R8b and the nitrogen atom, to which both are bound, means pyrrolidino or morpholino,
R8b Methyl oder gemeinsam mit R8a und dem Stickstoffatom, woran beide gebunden sind, Pyrrolidino oder Morpholino bedeutet, R9 Wasserstoff bedeutet,R8b is methyl or together with R8a and the nitrogen atom, to which both are attached, denotes pyrrolidino or morpholino, R9 denotes hydrogen,
R10 Wasserstoff bedeutet und n die Zahlen 0 oder 1 darstellt, und die Salze dieser Verbindungen.R10 represents hydrogen and n represents the numbers 0 or 1, and the salts of these compounds.
7. Verbindungen nach Anspruch 1 oder 2 oder 3 oder 4 oder 5 oder 6, worin n die Zahl 0 darstellt, und ihre Salze. 7. Compounds according to claim 1 or 2 or 3 or 4 or 5 or 6, wherein n represents the number 0, and their salts.
8. Verbindungen nach Anspruch 1 oder 2 oder 3 oder 4 oder 5 oder 6, worin n die Zahl 1 darstellt, und ihre Salze.8. Compounds according to claim 1 or 2 or 3 or 4 or 5 or 6, wherein n represents the number 1, and their salts.
9. Verfahren zur Herstellung der Verbindungen der Formel I nach Anspruch 1, dadurch gekennzeichnet, daß man9. A process for the preparation of the compounds of formula I according to claim 1, characterized in that
a) Mercaptobenzlmidazole der Formel II mit 2-Pyridylverbindungenn III,a) mercaptobenzlmidazoles of the formula II with 2-pyridyl compounds III,
oder b) Benzimidazole der Formel IV mit Mercaptopicolinen V, or b) benzimidazoles of the formula IV with mercaptopicolins V,
oder c) o-Phenylendiamine der Formel VI mit Ameisensäurederivaten VII or c) o-phenylenediamines of the formula VI with formic acid derivatives VII
umsetzt und (falls Verbindungen der Formal I mit n=1 die gawüntchten Endprodukte sind) anschlleßend die nach a), b) oder c) erhaltenen 2-Benzimidazolyl-2-pyridylmethyl-sulfide der Formel VIII (=Verbindungen der Formel I mit n=0) and (if compounds of the formula I with n = 1 are the desired end products) then the 2-benzimidazolyl-2-pyridylmethylsulphides of the formula VIII (= compounds of the formula I with n = 0)
oxidiert und/oder gewünschtenfalls in die Salze überführt, oder daß manoxidized and / or, if desired, converted into the salts, or that one
d) Benzimidazole der Formel IX mit Pyridinderivaten Xd) Benzimidazoles of the formula IX with pyridine derivatives X
oder e) Sulfinylderivate der Formel XI mit 2-Pyridylverbindungenn XII or e) sulfinyl derivatives of the formula XI with 2-pyridyl compounds XII
umsetzt und gewünschtenfalls anschließend in die Salze überführt, oder implemented and, if desired, subsequently converted into the salts, or
f) - falls Verbindungen der Formel I, worin R5 eine unter physiologischen Bedingungen leicht abspaltbare Gruppe darstellt, die herzustel- lenden Verfahrensprodukte sind - daß man Verbindungen der Formel I, worin R5 Wasserstoff bedeutet, mit Verbindungen der Formel R5'-Y' (XIII), worin R5' die gewünschte, unter physiologischen Bedingungen leicht abspaltbare Sruppe oder gemeinsam mit Y' ihr Vorläufer ist, umsetzt und gewünschtenfalls anschlleßend in die Salze überführt, oderf) - if compounds of the formula I in which R5 is a group which can easily be split off under physiological conditions are the process products to be prepared - that compounds of the formula I in which R5 is hydrogen are mixed with compounds of the formula R5'-Y '(XIII ), in which R5 'is the desired group which can easily be split off under physiological conditions or, together with Y', is its precursor and, if desired, is subsequently converted into the salts, or
g) - falls Verbindungen der Formel I, worin R5 Wasserstoff bedeutet, die herzustellenden Verfahrensprodukte sind - daß man Verbindungen der Formel I, worin R5 eine unter physiologischen Bedingungen leicht abspaltbare Gruppe darstellt, solvolysiert, und die erhaltenen Produkte gewünschtenfalls in die Salze überführt, oderg) - if compounds of the formula I, in which R5 is hydrogen, are the process products to be prepared - that compounds of the formula I, in which R5 is a group which can be readily split off under physiological conditions, are solvolysed and the products obtained, if desired, converted into the salts, or
h) - falls Verbindungen der Formel I, worin R6 C1-C6-Alkyl bedeutet, die herzustellenden Verfahrensprodukte sind - daß man Verbindungen der Formel I, worin R6 Wasserstoff bedeutet, mit Verbindungen der Formel R6-Y'' (XIV), worin R6 C1-C6-Alkyl bedeutet, alkyliert und gewünschtenfalls anschließend in die Salze überführt,h) - if compounds of the formula I in which R6 is C 1 -C 6 -alkyl are the process products to be prepared - that compounds of the formula I in which R6 is hydrogen are reacted with compounds of the formula R6-Y '' (XIV), wherein R6 is C 1 -C 6 alkyl, alkylated and, if desired, subsequently converted into the salts,
wobei Y, Y*', Z, Z' und Z'' geeignete Abgangsgruppen darstellen, Y' eine Abgangs- bzw. Reaktivgruppe darstellt, M für ein Alkalimetallatom (Li, Na oder K) steht, M' für das Äquivalent eines Metallatoms steht und R1, R2, R3, R4, R5, R6, R7 , R8a, R8b, R9, R10 und n (sofern nicht anders definiert) die in Anspruch 1 angegebene Bedeutung haben. where Y, Y * ', Z, Z' and Z '' represent suitable leaving groups, Y 'represents a leaving or reactive group, M stands for an alkali metal atom (Li, Na or K), M' stands for the equivalent of a metal atom and R1, R2, R3, R4, R5, R6, R7, R8a, R8b, R9, R10 and n (unless otherwise defined) have the meaning given in Claim 1.
10. Verbindungen nach einem oder mehreren der Ansprüche 1 bis 8 und ihre pharmakologisch varträglichen Salze zur Anwendung bei der Behandlung und/oder Prophylaxe von Krankheiten des Magens und/odar Darms und solcher Krankheiten, die auf einer erhöhten Magensäuresekretion beruhen.10. Compounds according to one or more of claims 1 to 8 and their pharmacologically acceptable salts for use in the treatment and / or prophylaxis of diseases of the stomach and / or intestine and those diseases which are based on increased gastric acid secretion.
11. Arzneimittel enthaltend eine oder mehrere Verbindungen nach einem oder mehreren der Ansprüche 1 bis 8 und/oder ihre pharmakologisch verträglichen Salze.11. Medicament containing one or more compounds according to one or more of claims 1 to 8 and / or their pharmacologically acceptable salts.
12. Verwendung von Verbindungen nach einem oder mehreren der Ansprüche 1 bis 8 und/oder ihren pharmakologisch verträglichen Salzen zur Herstellung von Arzneimitteln für die Behandlung und/oder Prophylaxe von Krankheiten des Magens und/oder Darms und solcher Krankheiten, die aff einer erhöhten Magensäuresekretion beruhen. 12. Use of compounds according to one or more of claims 1 to 8 and / or their pharmacologically acceptable salts for the manufacture of medicaments for the treatment and / or prophylaxis of diseases of the stomach and / or intestine and such diseases which are based on increased gastric acid secretion .
EP85905795A 1984-10-31 1985-10-29 New amino compounds, preparation process thereof, utilization thereof and drugs containing them Withdrawn EP0200777A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH522584 1984-10-31
CH5225/84 1984-10-31

Publications (1)

Publication Number Publication Date
EP0200777A1 true EP0200777A1 (en) 1986-11-12

Family

ID=4290039

Family Applications (1)

Application Number Title Priority Date Filing Date
EP85905795A Withdrawn EP0200777A1 (en) 1984-10-31 1985-10-29 New amino compounds, preparation process thereof, utilization thereof and drugs containing them

Country Status (6)

Country Link
EP (1) EP0200777A1 (en)
AU (1) AU5092985A (en)
GR (1) GR852630B (en)
IL (1) IL76837A0 (en)
PT (1) PT81397B (en)
WO (1) WO1986002645A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JO1406B1 (en) * 1984-11-02 1986-11-30 سميث كلاين اند فرينش لابوراتوريز ليمتد Chemical compounds
NZ242756A (en) * 1991-06-03 1994-07-26 Sumitomo Chemical Co Benzimidazole derivatives having a fused ring which contains 1 or 2 o atoms and at least 1 -cf2- unit; use as fungicides; and precursors
DE19745692A1 (en) * 1997-07-24 1999-01-28 Bayer Ag Process for the preparation of 2-chloro-benzimidazole derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8602645A1 *

Also Published As

Publication number Publication date
GR852630B (en) 1986-02-03
AU5092985A (en) 1986-05-15
WO1986002645A1 (en) 1986-05-09
PT81397B (en) 1987-08-04
IL76837A0 (en) 1986-02-28
PT81397A (en) 1985-11-01

Similar Documents

Publication Publication Date Title
EP0201575B1 (en) New picoline derivatives, preparation process thereof, utilization thereof and drugs containing them
EP0166287B1 (en) Dialkoxyridines, process for their preparation, their application and medicaments containing them
EP0134400B1 (en) Fluoroalkoxysubstituted pyridylmethylthio-(or sulfinyl-)benzimidazoles having a secretolytic activity
EP0080602A1 (en) Substituted benzimidazoles, process for their preparation, their use and medicaments containing them
EP0127763B1 (en) Tricyclic ethers, process for their preparation, their use and medicaments containing them
DE3132613A1 (en) IMIDAZOLE DERIVATIVES
JPS6122079A (en) Dialkoxypyridine, manufacture, use and drug
WO1989005299A1 (en) Novel benzimidazole derivatives
DE3415971A1 (en) Acylated benzimidazoles, processes for their preparation, their use and medicaments containing them
EP0200777A1 (en) New amino compounds, preparation process thereof, utilization thereof and drugs containing them
WO1989011479A1 (en) New fluoralkoxy compounds
EP0657459A1 (en) Thienothiazine derivates, process for their preparation and their use as anti-inflammatory and analgesic agents
EP0232399A1 (en) New amines, process for their manufacture, their use and medicines containing them
EP0180833B1 (en) 4-Oxo-pyrido-[2,3-d]pyrimidine derivatives, process for their preparation and medicaments containing them
DD259401A5 (en) PROCESS FOR THE PREPARATION OF 2-ALKYLBENZIMIDAZOLE DERIVATIVES
DE2446495A1 (en) NEW PYRAZOLO (3,4-B) THIENO (2,3-D) PYRIDINE-2-CARBOXYLIC ACIDS AND ACID ESTERS
DE4425647A1 (en) Heterocyclyl-1-phenyl substituted quinolonecarboxylic acids
EP0882048A1 (en) 3-methylimidazopyridines
DE3343884C2 (en)
DE2428640A1 (en) ANTHELMINTIC COMPOUNDS AND PROCEDURES FOR THEIR PRODUCTION
DE4425660A1 (en) 7-Substituted 1- [4- (1H-1,2,4-triazol-1-yl-methyl) phenyl] substituted quinolone carboxylic acids
DE3701737A1 (en) 1H-Pyrido[2,3-b][1,4]thiazines for therapeutic treatment
DD273257A5 (en) METHOD FOR PRODUCING SPECIFIC BENZOTHIAZINES
WO1997027193A1 (en) Imidazopyridine halides

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19861001

RIN1 Information on inventor provided before grant (corrected)

Inventor name: RAINER, GEORG

Inventor name: SENN-BILFINGER, JOERG

Inventor name: FIGALA, VOLKER

Inventor name: RIEDEL, RICHARD

Inventor name: KOHL, BERNHARD

Inventor name: SCHAEFER, HARTMANN

Inventor name: KLEMM, KURT